IE901563L - Heterocyclic n-oxide derivatives of substituted¹benzo(5,6)cycloheptapyridines, compositions and methods of¹use - Google Patents

Abstract

Heterocyclic N-oxide derivatives of substituted benzo[5,6]cycloheptapyridines, and pharmaceutically acceptable salts and solvates thereof are disclosed, which possess anti-allergic and anti-inflammatory activity. Methods for preparing and using the compounds are also described.

Description

6 6 3 9 2 i 5 10 HETERQCYCLSC N-OXIOE DERHVATIIVES OF SUBSTITUTED BENZQ[5,6]GYCLQHEPTAFYRIDINES. COMPOSITIONS AND METHODS OF USE 15 BACKGROl IMP OF THE INVENTION The present invention relates to heterocyclic N-oxide derivatives of substituted benzo[5,6]cydoheptapyridines and to pharmaceutics! 'Compositions and methods of using such (compounds. 20 United States Patents 3,326,924,, 3,717,647 and 4b282s2339 European published Application No. 0042544 and Villani et al.f Journal of Medicinal Chemistry. Vol 15, No. 7E pp 7SQ-754 (1972) and Aran. Forch 36 1311-1314 (1986) describe certain 11-{4-piperidylidene)-5Ji-benzo[5,6]cyclohepta[182-Eo]pyridines as 25 antihistamines. U.S. Patent 4,355,036 describes certain ^-substituted piperidylidene compounds.

WO 88/03138 discloses compounds of the formula fr, I CD o y v 2 R2-—" \^R7 or a pharmaceutical^ acceptable salt or solvate thereof, wherein: one of a, b5 c and tJ represents N or !MR® where r9 is O 5 -CH3 or -(CHg)nCOoH where n is 1 to 38 and the remaining a, b9 c and d groups are CH, which remaining a. b, a and d groups optionally may be substituted with or IR2; R,1 and r2 may be the same or different and each independently represents halo, -CFg, -GFfi0a -COR10, -SR1®, -KI(B10)2, 10 -N02s -0G(0)R"10, -COaFf1 Q -0C02R11, alkyrwl, aikenyl or aikyl, which alkvl or aikenyl group may be substituted with halo, -OR10 or -OQ2R o A R and R: may be the same or different and each 1 ^ independently represents IHI, any of the substituents of R and R29 or R and R4 together may represent a saturated or unsaturated fused C5-C7 15 ring ; R5, R6, R7 and R8 each independently represent H, -CF3, alkyl or aryl, which alkyl or aryl may be substituted with -OR^O, ~SR^s -N(R1C))2, -NO2, -COR1®, -OCOR10, -OCO2R11. -C02R10. -OPO3R10 or one of R®,„ R®9 R7 and R® may be taken in combination with R as defined 20 below to represent -(CH2)r w/here r is 1 to 4 which may be substituted with lower alkyl, lower alkoxy, -CFg or aryl; Rl 0 represents H, alkyi or aryl; R'^ represents alkyl or aryl; X represents N or C, which C may contain an optional double bond to carbon atom 11; the dotted line between carbon atoms 5 and 6 represents 5 an optional double bond, such that when a double bond is present, A and B independently represent H, -pJ®, -QpJ ^ or -OG(o)R"®0, and when no double bond is present between carton atoms 5 and S9 A and B each independently represent H2> -(GR^Jp, alkvi and H, {alkyl)^, -Hi and •OC(0)R1°, H and OR10, «09 aryl and H, =NOB10 or -0-(CH2) -O- 10 10 where p is 2,3 or 4 and R is as previously defined; Z represents O, S or H2 such that g (a) when 2 Is Q, B may be taken m oombination with R , R68 R7 or R® as defined abovea or R represents H, aryl,, alkyl, ~sri 3, ~N(r'®)2, cycloalkyl, aikenyl, alkynyl or -D wherein -D represents 15 heterocycloalkvl, wherein R3 and R4 are as previously defined and W is O, S or NR1 ® 20 wherein R10 is as defined above, said cycloalky!, alkyl, aikenyl and alkynyl being optionally 10 substituted with from 1-3 groups selected from halo, -GON(R )9, aryl, -CO2B10e -OR12s -SB12, -M(R10)2, -n(r10)co2r10, -GOB12, -no,, or in 19 "i n -D, wherein -D and R are as defined above and R "" represents R , 4 ~(CP;?)mORi0 or-(CH?) COgRi0 wherein R10 is as previously defined, iffi is 1 to 4 and q is 0 to 4, said aikenyl and alkynyl R groups not containing -OH, -SH 10 or -N(R )2 on a carbon containing a double or triple bond respectively; 5 (b) when Z represents S, R represents la addition to those R groups above, suyloxy or alkoxy; and (c) when Z represents R represents -GQQR i08 -E-COOR'0 or -E-QR1" where IE is alkanediyl which may be substituted with -OR10, -SR10„ -N(R10)2 or -D where Ds R10 and R12 are as 10 previously defined. These compounds are disclosed as Toeing useful in the treatment of allergy and inflammation.

SUMMARY OF THE INVENTION 15 We have mow surprisingly found that N-oxide compounds having the structural formula i below possess both patent antihistamine and PAF antagonistic activities: 20 C'/N | a I: - -R7 or a pharmaceutical^ acceptable salt or solvate thereof, wherein: R represents an N-oxide heterocyclic group of the formula 0). (H). (Hi) or Civ) I R® R® O (Tn^nO |fX % Rl° b \J' l/\Jy ./***%» Rtc/^\ - Rii © 0i) R® O .N.

R10 or Cm) R" R\ 0 .N r p;J0"r'%^\rj (iv) 10 15 20 25 30 or R represents a straight or branched to C20 alkyl group substituted with a heterocyclic N-oxide group of the formula (i)s (ii)» (iii) or (iv) above; _ "3 9 10 ome of a b, c and d represents N or-NRwhere FF~ is O, -CH. or -(CH^COpH where n f III to 3, ai the remaining a, b,-c and d groups are CH, which remaining b, c and d-grotaps optionally may be sybslitutecl with or P?; IB1 and ft2 may be the same or cBffererrt and each' independently represents halo, -CF3, -OK1'^ -GOR"i'1', -SRW, -S(0)JRm where e Is l.or 2, -N(RU)2, NQ^-OCCOJR13, -rCO#*3, -OCO^t1*, a straight or branched. C% t© Cu -aikenyl group, containing- at least one carbon to carbon double bond# a straight or branched C2-to Clz alkynyl group, containing at least oae carbon to carbon triple bond or a straight or branched Cx to C^o alkyl group, which alky! group may b® substituted with halo, -OR13 or «C02R13 and 'which aikenyl group may be substituted with halo, -OR14 or -C02R°i E3 and E4 -sway- be- the same or different and each independently represents H or any of the substituents of Rl and R2, or R? and a4 together may represent a saturated or unsaturated C3-C7 carbocylic ring fused to the benzene ring; R5, R5, R7 and R8 each independently represent E, -CFS, a straight or branched C» to C20 alkyl group or a C* to €w aryl 10 6 13 group which alScyl or aryl group being optionally substituted with -OR , -SR13 or -M(R*3)2, and said aryl group also being optionally substituted with one or more halo, straight or branched to C2g alkyl, hydroxy, straight or branched Cj to C20 alkoxy, phenoxv, CFg, amino, straight or branched to C20 alkylami no, straight or branched C1 to C20 dialkylamino, -C00R15 as defined below or 410 2e C Q in addition, R may be combined with R to represent =0 or =S 1 8 and/or R may be combined with R to represent =0 or =SE" q in i i R , R and R may be the same or different and each is 1 *3 I "3 independently selected from H, halo, -CFg, -OR , -C(0)R , -SR" , ~S(0)eR14 where e is 1 or 2, -N(Ri3)2, -M02, -C02R13, -OC02R14, -0C0R13, straight or branched C1 to C2q alkyl, Cq 15 to aryl group being optionally substituted with one or more halo, straight or branched Cj to C2q alkyl, hydroxy, straight or branched Cj to C20 alkoxy, phenoxy, CFg, amino, straight or branched to C20 alkylami no, straight or branched to C20 dialkylamino, -COOR^ as defined below or -M02 aryl, straight or branched C2 to 20 C19 aikenyl or straight or branched C0 to C19 alkynyl, which alkyl it) 1 O 1*3 or aikenyl may be substituted with -OR , -SR or -IN(R~ )9 and 14 14 which aikenyl may be substituted with OR" or SR"'t; 13 R represents H, straight or branched to C2g alkyl or Cg 25 to Cjg aryl group being optionally substituted with one or more halo, straight or branched to C20 alkyl, hydroxye straight or branched Cj to C2q alkoxy, phenoxy, CFg, amino, straight or branched to C2q alkylamino, straight or branched to C2q dialkylamino, -COOR1^ as defined below or aryl,: 30 14 R ' represents straight or branched to C9q alkyl or Cg to Cjg aryl group being optionally substituted vrith one or more halof straight or branched Cj to C2q alkyl, hydroxy, straight or branched Cj to C2Q alkoxy, phenoxv, CF^, amino, straight or branched C1 to 35 C2q alkylami no, straight or branched C1 to C2q dialkylamino, -C00R^ as defined below or -4!02 arylL: 15 R represents H or straight or branched to C9q alkyl; 7 X represents N, CH or Ce° when X represents C, an optional double bond indicated by the dotted lines to carbon atom 11 is present, and when X is N or CH, the double 5 bond is absent; the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B each independently represent ~R"3, halo, -OR"^, 0C(0)R~3 or -0C02R~^ 10 and when no double bond is present between carbon atoms 5 and 6, A and B i a each independently represent H2, -(0R"')2, [H and halo], dihalo, [straight or branched C^ to C2q alkyl and H], (straight or branched Cj to C2Q alkyl)2, [-H and -0C(0)R"3]e [H and -OR"3], =0, [aryl and H], =M0R'"^ or -0 (C'-'2)p"0~ where p is 2, 3 or 4 and R^3, Cg 15 to Cjg aryl group being optionally substituted with one or more halo, straight or branched C^ to C2q alkyl, hydroxy, straight or branched Cj to C2q alkoxw, phenoxy, CF^, amino, straight or branched Ct to C2q alkylamino, straight or branched C1 to C2q dialkylamino, -C00R15 as defined below or -t*K)2 aryl and straight or branched Cj 20 to C£0 alkyl and Z represents =0.

Preferably, b, c and d are CH| © is N or N+-0~; R~ and R^ each independently represent H, alky] (e,g», CHg), OH or halo^ the dotted lines between positions 5 and 6 are absent and A and B are both 25 [H, H] or one of A or B is [He OH] and the other represents [H,H] or the dotted line between positions 5 and 5 is present and A and B are both H; 3 A R and R' each independently represent H, halo or alkyl, most c g 7 preferably halo, e-g.,, chloro in the 8-position; R , R , R , and 8 R each represent H; and X represents C and the dotted line drawn to X 30 represents a double bond or X represents N and the dotted line is absent- A preferred embodiment of the invention involves compounds of the formula lb: 35 8 whera R' and R" are independently Ht Eialo„ alkyll, OH or CF3; R3 and R4 are the seme or different and are as defined above, preferably H or halo, e.g., shloro in the 8-position; and R in formula ib represents a 5 heterocyclic N-oxide group of the formula (i). (ii)9 (Hi) or (8v) above, or alb/I substituted with a heterocyclic N-oxide group of the formula (i), (ii), (iii) or (iv) above.

Preferably one or both of R3 and FIT as halo, e.g., chloro or fluoro. The most preferred value of R and/or RT us a halogen located at 10 cartoon atom 8 and/or 9S as shown in the following numbered ring structure showing the tricyclic portion of the compounds of the invention: 1 10 15 Compounds of the invention include: 9 I * rv« o a 10 r-*~© il ## I * Qji 5 n 12 O n' r-»-o O' 1 I i ch, 13 CH/ ,n+-*-0" rv? Particularly preferred compounds include: 14 r" N N and O N+^O' CHI. l3\#' n+-j»-0" 15 Tha snvention also is directed at a process for producing a compound having structural formula I wherein the substituents are as previously defined by: a) reacting a compound of formula ix below with a compound of formula RCOOH in the presence of a coupling agent I t~~^r rcooh i; X. n5^f^ % ' s' I! i H -R7 ■R8 II b) reacting a compound of formula n with a compound of 10 formula nx in the presence of base to produce compounds of structural formula i R2-—' rc(0)l III 15 wherein L designates a leaving group such as halo, e.g., CI; or 16 c) a compound of formula IV can be reacted with an oxidizing agent such as meta-chloroperbenzoic add (MCPBA) or hydrogen peroxide in acetic acid to form a compound of formula I R2—~" wherein Ra represents (Usually, oxidation of other basic amino groups in the molecules also occurs in this last process.) The invention also encompasses a pharmaceutical composition which comprises a, compound of formula I as defined above 15 in combination with a pharmaceutical^ acceptable carrier.

Tha invention further encompasses a compound of formula I for use in treating allergy or inflammation*, respectively. 17 The invention also comprises a method for making a pharmaceutical composition comprising mixing a compound of formula I whh a pharmaceutical^ acceptable carrier.

As used herein, the following terms are used as defined 5 below unless otherwise indicated: alkyl - (including the alkyl portions of alkoxy, alkylamino and dialkvlamino) - represents straight and branched carbon chains and contains from one to twenty carbon atoms, preferably on® to six carbon atoms; 10 cycloalkyl - represents saturated carfoocyclic rings branched or unbranched of from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms; 1 aikenyl - represents straight and branched carbon chains having at least one carbon to carbon double bond airad containing from 2 15 to 12 carbon atoms, preferably from 3 to 6 carbon atoms; alkynyl - represents straight and branched carbon chains having at least one carbon to carbon triple bond and containing from 2 to 12 -carbon atoms, preferably from 2 to 6 carbon atoms; aryl (including the aryl portion of aryloxy) - represents a 20 carbocyclic group containing from 6 to 15 carbon atoms and having at least on® phenyl! or fused phenylene ring* with al! available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted with one or more of halo, alkyl* hydroxy, alkoxy, phenoxy., GF^, amino, 25 alkylamino., dialkylarnino, -COOR'5 or-MOg; substituted phenyl - represents a phenyl group in which 1 to 3 hydrogen atoms thereof are replaced by the same or different substituents independently chosen from hydroxy, alkyl, halo, nitro, alkoxy, trifluoromethyl, cyano, cycloalkyl, alkenyloxy, alkynyloxy, SHs 30 S(0)pRa [wherein p is 0,1 or 2 and Ra us alkyil or arvl]; and halo - represents fluoro, chloro, bromo and iodo.

Certain compounds of the invention may exist in different isomeric (e.g., enantiomers and cfiastereoisomers) as well as conformational forms. The invention contemplates all such isomers both 35 in pure form and in admixture, including racemic mixtures. 18 The compounds of the invention of formula i can exist in unsoivated as well as solvated forms, including hydrated forms, e.g., hemihvdrate. In general, the solvated forms, with pharmaceutical^ acceptable solvents such as water, ethanol and tha like are equivalent 5 to the unsoivated forms for purposes of the invention., As noted above, the pyridine and benzene sing stasctures of formula I may contain one or more substituents Rj „ B2t and FT. in ..compounds where there is more than one such substituent, they may be the same or different Thus compounds having 'Combinations of such 10 substituents are within the scope of the invention. Also, the !ines drawn into the rings from the R! „ R2, and R** groups Judicata that such groups may be attached at any of the available positions. For example, 1 -9 the R and R groups may be attached to a carbon atom at the 18 2a 8 or 4 positions -while the R and R; groups may be attached at any of the 7S 15 8„ 9 or 10 positions.

IB,5, r6, r7 or R® are attached to the poperidyl, piperidylidenyl or piperazinyl ring. As such they may be the same or different Hie variables r5„ ir65 pj or p8s fa addition to representing H8 may represent variables attached to the sarnie or different carbon atoms 20 an said ring. For example, when and R®„ or R? and R® are combined to represent «0 or they are attached to the same carbon atom.

The N-oxides are illustrated herein using the terms INiO, IM~>Os N-0 and N+O" All are considered equivalent as used herein.

Certain compounds of the invention will be acidic in nature, 25 e.g. those compounds which possess a carboxyl or phenolic lhydroxyl group. These compounds may form pharmaceutical^ acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutical^ acceptable amines such as ammonia, alkyl 30 amines, hydroxyalkylamines, M-methyiglucamine and the like.

Certain basic compounds of the Invention also form pharmaceutical^ acceptable salts, e„g.s acid addition salts and quaternary ammonium salts. For example, the pvrido-nitrogen atoms may form salts with strong acid, while compounds having basic substi-35 tuents such as amino groups also form salts with weaker acids. 19 Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and earboxylie acids well known to those in the art. The salts sr© prepared 5 by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The quaternary 10 ammonium salts are prepared by conventional methods, e.g., by reaction of a tertiary amino group in a compound of formula i with a quaternizing compound such as an alkyl iodide, etc. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but flue salts are 15 otherwise equivalent to their respective free base forms for purposes of the invention.

All such acid, base and quaternary salts are intended to be pharmaceutical^ acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the wee forms of the 20 corresponding compounds for purposes of the invention.

The following processes may be employed to produce compounds of general structural formula I A. A compound of general formula S may be coupled with a compound of the formula RCOOH in the presence of coupling agent 25 such as 1-(3KJimethylaminopropyl)-3-ethyl carbodiimde hydrochloride (DEC), !^,M'-di(yclohexylcai1)odiimide (OCC) or N,N'-carbonyl-cfiimidazole (CDS) to produce compounds of general structural formula I: I 20 I . 10 The reaction is usually conducted in an inert solvent such as tetrahydrofuran or methylene chloride at a temperature between about 0°C and reflux, preferably at about room temperature. When the coupling agent is DCC or DEC. the reaction is preferably run in the presence of 1 -hydraxyhenzotriazole (HOST). Method A is the method of choice for preparing the compounds of the invention- B. A compound of formula M may also be reacted with a compound of formula 3H in the presence of base to produce compounds of structural formula I: j^2.——"V R4 + RC(0)L Hi I 15 Representative examples of appropriate bases are pyridine and triethylamine. L designates a suitable leaving group. For example, a 21 10 compound of compound HI may be an acyl halide (e.g., L represents halo) or an acyl anhydride^ (e.g., L Is -OC(O)-R). The leaving group may also be alkoxv, in which case the compounds of formula I may be produced by refluxing a compound of formula M with an excess of a compound of formula HI. compound of formula V below, by the methods described in WO 88/03138: wherein Rb represents alkyl or suyl, e.g., ethyl, 2,2,2-frichloroethyl or phenyl. 0. Alternatively, a compound of formula W can be reacted with an oxidising agent an inert solvent such as meta-chloroperbenzoic acid (MCPBA) m methylene chloride or hydrogen peroxide in acetic acid to form a compound of formula I: Compounds of general formula II may b© prepared from a 1 CQORb V 22 R2-" 1 wherein Ra represents Rl >•» >\ % J: ...vJ: >-x" Rio- - R11 R10' Rn (11) OH) R'''3 R9. if R10' 1/ \ V/ \. />scJ5!,s "N J (iv) The reaction is usually conducted anywhere from -1S°C to reflux. This method may also oxidize other basic amino groups on the compounds of formula I 10 The compounds of formula IV can be prepared employing the methods A and B above, but using compounds of the formula RaCOOH or RaCOL in place of the compound of HL The compounds of formula IV imay also be prepared by reacting a compound of formula VI with a compound of formula RaCOL: 15 23 R^COL IV . heat Preferably the reaction is run an the presence of an appropriate nucleophile (e.g. Lil, etc.) an an inert solvent (e.g., toluene, dioxane or 5 xylenes). L is a suitable leaving group such as halo or 0C(0)Ra. An appropriate base, may Ibe added, and heating is usually required. Typically, a temperature ranging from 50-150°C (preferably 100~120°G) is utilized'depending on the boiling point of the so!vent. The compounds of formula VI can be prepared as described in WO 88/03138. 10 Bn general, WO 88/03138 describes the starting materials for use in preparing the compounds of the invention. Rather than repeat those process details here, reference is made to pages 13-38 of WO 88/03138 for that purpose. For example, WO 88/03138 discloses how to make the starling materials having a double bond in the 5-6 bridgehead 15 position, having a double or single bond at the 11-position of the tricyclic ring system, having pipeiazine groups attached at the 11-position of the tricyclic ring system, having substitution on the bridgehead carbon atoms 5 and/or 6, and/or having-various R1, R2, R3, and/or R4 substituents on the tricyclic portion of the compounds of the invention, 20 etc. Sn addition to these, the following methodologies can be employed to prepare compounds of the invention having the tricyclic ring IN atom M-oxidized and/or having R1 and/or R2 substituents on the pyridine ring of the tricyclic ring system in the compounds of the invention. 24 PREPARATION OF PYRIDINE M-QXIOES The corresponding Nl-oxides of the invention (e.g., when a, b8 c or d in formula I is M M)" can be prepared by treating the 5 corresponding non-oxidized compound (provided that X is carbon) with an appropriate oxidizing agent in an inert solvent Suitable oxidizing agents are 3-^hloroperoxybenzoic acid in methylene chloride or peracetic acid in acetic acid. The reaction is usually carried out at low temperature (e.g. -10°Q) in order to minimize the formation of side 10 products, although higher temperatures are sometimes employed, if X=N, then this nitrogen may be protected as its salt or other complex (e.g.., complex with BF3) before oxidation. 15 substitution on the pyridine ring Various methods can be used as described in WO 88/03138 to provide compounds which are substituted on the pyridine ring, i.e., in positions 2~, 3- and or 4- positions of the tricyclic ring system. For example, the cyclization methods described on pages 20-30 of WO 20 88/03138 can already have the appropriate substituents on the pyridine ring in place. A variety of substituted pyridines are known in the literature and can b© employed in these syntheses. Alternatively, the azakeione of formula XIX (from page 27 of WO 88/03138) wherein R1 and R2 are both H can be converted to the appropriately substituted 25 azakeione where R1 and R2 are non-H substitutents. "If both Ft1 and R2 are desired to be non-H substitutents the procedure would be repeated.

The azaketone is thus reacted with an oxidizing agent such as meta-chloroperoxy benzoic acid (MCPBA) or hydrogen peroxide to produce the corresponding compound in which the nitrogen of the 30 pyridine ring is as an N-oxide: 25 XIX XlXa where on® of a\ bs8 € or cT is M—>0 .and the others are CH or CR1 or CR2. This reaction is normally am at temperatures from -15°G to reflux, more typically at about 0°C. The reaction is preferably conducted in an inert solvent such as methylene chloride for MCPBA or acetic acid for hydrogen peroxide.

The azaketone N-oxide of formula XDCa can then be reacted with a chlorinating agent such as SO2CI2 of SOCfeto form a compound of formula xixb. Typically, this reaction results m monosubstitution of CI in the ortho or para-position relative to the N atom of the ring.

XlXa XlXb To provide the disubstituted products,, steps 1 and 2 above are repeated. 26 Typically, the resulting disubstituted compounds have CI ortho and para relative to the N atom of the pyridine ring.

The mono or disubstituted compounds of formulas xixb 5 and xixc above can be reacted with various nucleophiles such as alkoxides, amines, thiols, etc. This will result in compounds where one or both of the CI substituents are replaced by the nucleophile to provide a compound of formula xixd or a compound easily converted to formula xixd.

XlXd The substituted ketone formula xixd can then be converted to the target compound of the invention by the methods 15 described above and in WO 88/03138 and in U.S. Patent Mo. 3,326,924. 6 XlXd Alternatively, the CI substituted azakeiones of formula 20 xixb or xixc above can be converted to the corresponding derivatives of formula n above Ft1 and/or R2 is CI by methods analogous to those described above. At this point the CI substitunt(s) can be displaced by an appropriate nucleophile to provide the desired subsiituani Suitable nucleophiles include alkoxide, amines, thiols, etc. This reaction usually 25 requires higher ternperturss (e.g., from about 100° to about 200°C) than 27 the displacement reaction io produce ketone xixd above, lit is also usually conducted in a sealed vessel in an inert solvent. The compound of formula n is then converted compound of formula i as described above. 5 Various ©lectrophilec species can also be added to the pyridine ring from the corresponding halo-substituted pyridine (formula H where R1 is halo9 preferably bromo or iodo). Transmetallation of the halo derivative using an alky! lithium (e.g. n-BuLi) provides the lithio derivative, which can then be quenched with the appropriate 10 eleciraphile (e.g. H''LS etc.).

Where Z represents sulfur, a compound of formula I where 2 is oxygen is reacted with PgSg, Lawesson's reagent, or another reagent capable of introducing sulfur in place of oxygen. The reaction may take place at elevated temperature in pyridine, toluene or other 15 suitable solvents- In this and other reactions, numerous conversions of a compound of formula i (2 = 0) to another compound of formula i (Z = S) are possible.

In the above processes, it is sometimes desirable and/or necessary to protect certain R*', H2 , R'3 and R4 etc., groups during the 20 reactions. Conventional protecting groups are operable as described in Greene, T.W., "Protective Groups On Organic Synthesis/5 John Wiley & Sons, Mew York, 1981. For example, the groups listed in column 1 of the following table may be protected as indicated in column 2 of the table: 28 table 1. EEQTEQTEP_Q.BQ.UES 1. GRO'OP TO BE PROTECTED 2. PROTECTED GROUP -cooh -COOalkyl, -COObenzyl, -COOphenyl, ch3 ^NH ^NCOalkyl, ^NCObenzyl.

^NCOphenyl \ ^co O'—%, x X' >0 0—f Or -oh —O—( y , -OCH2phenyl, O-—3 -OCHg, OSi(CHg)2(t-Bu)s -NHR, wherein R is any substituent on an amino group within the scope of the claims ' / \ —N—{ } ' R W -NR-C0-CF3, -NRCOCH3, f -mh2 0 —N V- 0 -NH-C(0)-0(t-Bu) 29 Other protecting groups m?ell known in the art also may be used. After the reaction or reactions, the protecting groups may be removed by standard procedures.

The compounds of the invention possess platelet-5 activating factor ("PAP) and histamine antagonistic properties, Th® compounds of the invention are8 therefore, useful when PAF and/or histamine are factors in th® disease or disorder. This includes allergic diseases such as asthma, adult respiratory distress syndrome, urticaria and inflammatory diseases such as rheumatoid arthritis and osteo* 10 arthritis, for example, PAF is an important mediator of such processes as platelet aggregation, smooth muscle contraction (especially an lung tissue), vascular permeability and neutrophil activation. Recent evidence implicates PAF as an underlying factor involved in airway hyperreactivity. 15 The PAF antagonistic properties of these compounds may be demonstrated by use of standard pharmacological! testing procedures as described below. These test procedures are standard tests used io determine PAF antagonistic activity and to evaluate the usefulness of said compounds for counteracting th® biological effects of 20 PAF. The Id, vitro assay is a simple screening test, while the jr» vivo test mimics clinical use of PAF antagonists to provide data which simulates clinical use of the compounds described herein.

A. In Vitro Studies 25 Platelet Aggregation Assav Platelet-activating factor (PAF) causes aggregation of platelets by a receptor-mediated mechanism. Therefore, PAF-induced platelet aggregation provides a simple and mnmnlem assay to screen compounds for PAF antagonism. 30 Human blood (50 ml) was collected from healthy male donors in an anticoagulant solution (5 ml) 'Containing sodium citrate (3.8%) and dextrose (2%). Blood was centriguged at 110 x g tor 15 min. and the supernatant platelet-rich plasma (PRP) carefully transferred into a polypropylene tube. Platelet-poor-plasma (PPP) was prepared by 30 eentrifuging FRP at 12,000 x g for 2 min. (Beckman fySicrofuge B)„ PRP was used within 3 hr. of drawing the blood.

PAF was dissolved in chlomformi:m@thanol (1:1, v/v) at a concentration of 2 mg/ml and stored at -70°C. An aliquot of this solution 5 was transferred io a polypropylene tube and dried under a flow of nitrogen gas. To the dried sample was added Hepes-saline-BSA (BSA = bovine serum albumen) buffer (25 mil Hepes, pH 7.4,1254 mM NaCI, 0.7 mM MgGl2 and 0.1% BSA) to obtain a 1 mi solution and sonicated for 5 min. in a bath sonieator. This stock solution was further diluted to 10 appropriate concentrations in Hepes-saline-BSA buffer. Collagen (Sigma) and adenosine diphosphate (ADP) (Sigma) were purchased as solutions. Test compounds were initially dissolved on dimethyl sulfoxide (DSwfSO) at a concentration of 50 mM and then further diluted in Hepes-saline-BSA buffer to achieve appropriate concentrations. 15 When an aggregating agent such as PAF is added to PRP, platelets aggregate. An aggregometer quantifies this aggregation by measuring and comparing light (infra-red) transmission through PPP and PRP. Aggregation assays were performed using a dual-channel aggregometer (Model 440, Chrono-Log Corp., Havertown, PA). PRP 20 (0.45 ml) in aggregometer cuvettes was continually stirred (37°C).

Solutions (50 p,L) of test -compounds or vehioel were added to the PRP and, after incubation for 2 min., 10-15 jul aliquots of PAF solution were added to achieve a final concentration of 1-5 x 10^ML Incubations were continued until the increase on light transmission reached a maximum 25 (usually 2 min.}. This increase in Sight transmission reflecting platlet aggregation is transmitted io a computer by th® Chrono-Log model 810 AGGRQ/UNK Interface. The AGGRO/UINK calculates the slope of transmission change, thus providing the rate of aggregation. Values for inhibition were calculated by comparing rates of aggregation obtained in 30 the absence and the presence of the compound. For each experiment, a standard PAF antagonist such as 8-chloro-6,11 -dihydro-11 -(1 -acetyl-4-piperidylidens)-5H=benzo[566]cyclohspta[152-b]pyridine was used as a positive control.

Compounds that inhibit PAF-induced aggregation were 35 tested against several other aggregating agents including collagent (0.2 31 mg/nnl) and ADP (2 ;juVi)., Compounds showing no activity against these latter agents were considered to be specific PAF antagonists. Results are shown in TABLE 2 below, 5 8„ lln Vivo Studies: Agonist-induced Responses Male Hartley guinea pigs (450-550 g) were obtained from 10 Charles River Breeding Laboratories. The animals ware fasted overnight and the following day were anesthetized with 0.9 ml/kg Lp. of dialurethane (containing 0.1 g/ml diallylbarbituric acid, 0.4 g/ml ethylurea and 0.4 g/ml urethane). The left Jugular vein was cannulated for the administration of compounds. The trachea was cannulated and 15 the animals were ventilated by a rodent respirator at 55 strokes/min. with a stroke volume of 4 ml. A side arm to the tracheal 'Cannula -was connected to a pressure transducer to obtain a continuous measure of inflation pressure. Bronchoconstriction was measured as the percent increase in inflation pressure that peaked within 5 min. after challenge 20 with spasrnogen. The animals were challenged Lv. with either histamine (10 ug/kg)a methacholin© (10 jjig/kg), 5~hydroxytryptamine (10 p.g/kg)r or PAF (0.4 :j.g/kg iin isotonic saline containing 0.25% BSA). Each animal was challenged with only a single spasrnogen. The effect of a compound on the bronchospasm is expressed as a percent inhibition of 25 the increase in inflation pressure compared io the increase in a control group. Results are shown in TABLE 2 below.

TABLE 2 R Q R1 R2 R3 Ft4 _X PAF Aniagonlsrn ^ 1-double (In vitro; PAF bond ICso (jxM) Oose °/o(nhlbit[on Doss %lnhibiUon CO ro I! , N H H CI H C N«-M> yes 0.2 lOmg/kg 100 lOmg/kg 90 II . N+0" H H CI H C yes 0.5 lOmg/kg 15 r q R1 R2 R3 Ft4 X v li . N * H ' Ci H C Y"ii M-t.^,0 N CH3 H CI H C f It . N H H CI H N N,fe*-0 -Cjf - tertiary butyi TABLi 2 Continued PAF Antagonism 11 -double (Jn vitro) bond iC50 (fifvl) Dose %inhibIlion Dose %lnhibition yes 1.0 3 mg/kg ' 40 yes 0.1 3 mg/kg 22 00 00 no 0.2 3 mg/kg 98 3 mg/kg 0 34 As seen from the data of TABLE 2 above, the compounds of structural formula I exhibit PAF antagonist and antihistamine properties to varying degrees, i.e., certain compounds have strong PAF 5 antagonistic activity, but have weaker antihistamine activity. Other compounds are strong antihistamines but weaker PAF antagonists. Several of the compounds are both strong PAF antagonists and potent antihistamines. Consequently, it is within the scop© of this invention to use each of these compounds when clinically appropriate. For example,, 10 if a strong PAF antagonist is required, but weaker arttihistaminic activity is necessary, such a compound could be chosen by th© clinician. Alternatively, if both potent PAF antagonism and antihistamine activity are required, a different compound of the invention would be utilized by the clinician. 15 For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaoeutically acceptable -carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from 20 5 io 70 percent active ingredient Suitable solid carriers are known in the art e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tabletss powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a Bow melting wax such as a 25 mixture of fatty add glycerides or cocoa butter Is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into (convenient sized molds, allowed to cool and thereby solidity.

Liquid form preparations include solutions,, suspensions 30 and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection.

Liquid form preparations may also include solutions for intranasal administration. 35 Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutical^ acceptable carrier, such as an inert compressed gas.

Also included are solid form preparations which are 5 intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of 10 creams, lotions, aerosols and/or emulsions and can be Included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is iro unit 15 dosage form, in such form, the preparation is subdivided Into unit doses containing appropriate quantities of the active component, ©-S-, an effective amount to achieve the desired purpose.

The quantity of active compound in a unit dose o! preparation may be varied or adjusted from about 0.1 mng to 1000 mg, 20 more preferably from about 1 rng. to 300 trig, according to the particular application. The appropriate dosage can be determined by comparing the activity of the compound with the activity of a known antihistamine compound such as 8-chioro-6911-dihydro-11-(1-ethoxycarbony!-4-piperidylidene)-5U-ben2o[5s8]GycSohepta[1a2-bjpyridine, which 25 compound is disclosed in U.S. Patent No. 4,282,233.

The actual dosage employed may fa© varied depending upon the requirements of th® patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with 30 smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. 36 Th© amount and frequency of administration of the compounds of the invention and the pharmaceutical^ acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the 5 patient as mfell as severity of the symptoms being treated. A typical recommended dosage regimen is oral administration of from 10 mg to 1500 mg/day preferably 10 to 750 mg/days in two to four divided doses to achieve relief of the symptoms. The compounds are non-toxic when administered within this dosage rang©. 10 The following examples are intended to illustrate, but not to limit, the present invention.

PREPARATIVE EXAMPLE I 15 A. N-(1 .1 -DlMETHYLETHYL>"3-METHYL"2-PYRIDINE IN) V MHO(CH3)3 20 Suspend 2~cyano~3~methyl pyridine (400 g) in t-butanol (800 mL) and heat to 70°C. Add concentrated sulphuric acid (400 ml) dropwise over 45 minutes. Maintain the temperature at 7S°C, .until th© reaction is complete, and for an additional 30 minutes. Dilute the mixture with water (400 ml), charge with toluene (600 mL) and bring to 25 pH 10 with concentrated aqueous ammonia. Maintain the temperature at 50-55°C during the work up. Separate the toluene phase, and reextract th© aqueous layer. Combine toluene phases and wash with water. Remove the toluene to yield the title compound M-{1 ,1-dimethylethyl)-3-ifnethyl-2-pyridine carboxamide, as an oil, fror^ which solid product is 30 crystallized. (Yield 97%, as determined by an internal standard assay with gas chromatography). 37 B. 3-f?-(3-CHI .OROPHENYUETHYLI-N-f 1.1-DiMETHYi .FTHYI .V-2-PYRIDiNF CARBQXAMIPE V NHC(C^)3 V^VCI w° ^ mciCHsh s A, IN Dissolve the title compound of Preparative Example it (ls1-dirnethylethyl)-3-methyl-2-pyridine carboxamide (31.5 g.) in tetrahydrafuran (600 mL) and cool the resulting solution to -4Q°G. Add n~butyllithium (2 eq„) in hexane while maintaining the temperature at - 4Q°C. The solution turns deep purple-red. Add sodium bromide (1.6 g) and stir the mixture. Add solution of sn-ehlorobeozyllchloilde (26.5 g., 0.174 mole) in mirahydrofumn (125 imL) while iTTnainfaliniiig the temperature at =40°C. Siir the reaction mixture until the reaction is complete as determined by thin layer chromatography. Add mater to the reaction until the color is dissipated. Extract the reaction mixture with ethyl acetate, wash with water, and concentrate to a residue which is the title compound. (Yield 92% as shown by chromatography).

C. 3-f2-^3"CHLOROPHENYOETHYU-2-PYRID8NE- 20 f*.Ai NHC(CP9)3 V^vci N^CN Heat a solution of the title compound of Preparative 25 Example 1B, 3-[2>(3-chlorophenyl)ethyl]-N-(1,1 -dimethylethyl}-2- pyridine carboxamide (175 g, 0.554 mole) in phosphorous oxychloride (52S imL, 863 g9 5.63 mole) and reflux for 3 hours. Determine completion of the reaction by thin layer chromatography. Remove any excess phosphorous oxychloride by distillation at reduced pressure and 38 quench the reaction in a mixture of water and asopropanoh Bring to pH 5-7 by adding 50% aqueous sodium hydroxide solution while maintaining the temperature below 3Q°C. Filter the crystalline slurry of crude product and wash with water Purify the caide product by 5 slurrying the wet cake in hoi isopropanoi, and cool to 0-5°C. Filter the product;, wash with hexane and dry'at a temperature below 50°C to yield the title compound. (Yield: 118g (HPLC purity 95,7%). rap. 72°O730C9 89.4% of theory). 10 0. 1 -fMETHYl r44>IPF:R11DINlYLV3-f2-(3- CHLOROPHFNY1AFTHYI .V2-PYRIOINYI IMFTHANONE HYDROCHLORIDE (118 g, 0.487 mole) in dry tetrahydrofuran (1.2L) and add N-imethyl~ piperidyl magnesium chloride (395 mL„ 2.48 mole/liter, 0.585 moles 1.2 eq.) over 15 minutes. Maintain th© temperature at 40°C-50°C''by cooling 20 with water as necessary, for 30 minutes. Determine completion of the reaction by thin layer chromatography. Quench the reaction by reducing the pH to bellow 2 with 2N HCI and stir the resulting solution at 25°C tor 1 hour. Remove the bulk of the tetrahydrofuran by distillation and adjust the resulting solution to pH 3.5 by addition of aqueous sodium 25 hydroxide. Cool to 0 to 5°C and filter off the crystalline hydrochloride salt product. Wash with ice cold water and dry to constant weight at 60°C to yield the title compound. (Yield: 168.2 g (HPILC purity 94%), m.p. 183°-1850C„ 89% of theory).

CBs 15 Dissolve the title compound of Preparative Example 1C, 39 E. 8-CHLORO-11 -(1 -METHYL-4-PIPERIPYLIDENE)-6.11 DiHYDRO-SH-RFiMZOrS.filOYCLOHFPTAfl .2-bl PYRIDINE Dissolve the title compound of Preparative Example 1D above (59 gs 0.15 mole) in hydrofluoric add (120 mL 120 g5 6.0 mote) at -35°C and add boron trifluoride (44.3 g, 0.66 mote) over 1 hour. Determine completeness of the reaction by thin layer chromatography. 10 Quench the reaction jsing See, water and potassium hydroxide bringing the solution to a final pH of 10. Extract the product with toluene and wash with water and brine. Concentrate the toluene solutiori to a residue, and dissolve in hot hexane. Remove the insolubles by filtration and concentrate the filtrate to yield the title compound as an'off-white 15 powder. (Yield: 45.7 g (HPLC purity: 95%)P 92% of theory).

Alternative Step E: 8-GHLORQ-1141 -METHYL-4-PIPERBPYIJDENEV8.11 -PIHYQRO-5H-BFNZQr5.6lGYCLQHEPTAf1 bIFYRIPINE 20 React the title compound of Preparative Example 1D above (177 g9 0.49 mole) in trifluoromethanesuHonic add (480 mi, 814.1 g, 5.31 mole) at 90-95°G for 18 hours under nitrogen. Determine the completeness of the reaction by thin layer chromatography. Cool tha 25 reaction and quench the reaction with ice-water and adjust tha pH to 6 with barium carbonate. Extract the product with methylene 'Chloride, and concentrate under reduced pressure to about 1 liter. Wash with water, and extract the product into 1 M HCI which is treated with 30 g of 40 activated charcoal, and filter through celite. Adjust the pH of the filtrate to 10 with aqueous sodium hydroxide (50%), extract the product into methylene chloride, and remove under reduced pressure io form a residue. Dissolve the residue in hot hexane, and filter to remove insolubles. Concentrate the filtrate to yield the title compound as a beige powder. (Yield: 126 g (HPLC purity 80%), 65% of theory).

F. 8-CHLORO-11 -t1 -FFHOXYCARBONYl_.-4" FIPFRIDYI 8.11-DIHYDRO-5H-BENZQr5-6lCYCLOHF:PTAri ?- 10 CX^CHgCHg Dissolve the title compound of Preparative Example 1E 15 above (45.8 g, 0.141 mole) in toluene (320 mil) at 80°C and to 5t gradually add ethyl chloroforrnate (40.4 mL, 45.9 g, 0.423 mole). Following complete addition, maintain the temperature at 80°C for 1 hour, then add diisopropylethylamine (2.7 mL, 2.00 g, .016 mole) and additional ethyl chloroforrnate (4.1 mL, 4.65 g, 0.0429 mole). (Monitor 20 completeness of the reaction by thin layer chromatography. Upon completion, cool the reaction mixture to ambient temperature, and wash the toluene solution with water. Concentrate the organic layer to a residue and dissolve in hot acetonitril© (320 mL). Decolorize the solution with 14 g of activated charcoal. Remove the activated charcoal by 25 filtration and concentrate the filtrate to a crystalline slurry. Cool the mixture to 0-5°C, and isolate the product by filtration. Wash with cold acetonitrile and dry the product at below 70°C to yield the title compound. (Yield: 42.4 g (HPLC purity 97.4%), 80% of theory). 41 G. R-CHIORO-11-(4-PIPFRlDYLIIDENIEV6.11-PIHYDRO- /Ors sicvni QHEPTAM 9-hlPYRIPIME CI C()2CH2CH3 H Hydrolize the title compound of Preparative Example 1 IF, flic 15 chloro-11 -(1 "ethaxycarbonyl-4-piperidySidene)-e911 ~dihyclr©-5H-berizo[5,6]cyclohepta(1,2-b]pyridine (39 g, 0.101 mole) with KQH (50 g) in ethanol (305 mL) and water (270 mL) at reflux under ara argon atmosphere for 84 hours. Partially distill off the ethanol and dilute the residue with brine, and extract with ethyl acetate (3x). Wash the combined organic phases with water and dry with Mla^SO^. Remove th® solvent to give a solid which can be reoystalfized from toluene to give the title compound as a white solid (Yield: 24.5 g, 77%, melting point 154-155°C). substituted benzylic halide listed in TABLE 3 below for inneta--chlorobenzylchiGride, and employing basically the same methods as steps C through G, the products listed in TABLE 3 below are prepared. Reaction times are determined by TLC or HPLC. In some instances purification of the product by chromatography is necessary.

M. By substituting in step 1B above, an appropriately 42 TABLE 3 Product of step G A j| halide R3 "^af " I J BT-^ u CI f*U.I lWiu ug Br H a h H OCH3 H *XOf?£ H H h m.p„ 133,5-134.5°08 15G-152°Cb 142-144°Cc 14S~148°C crude solid glass CI GH3 CHI3I - Then repeat step B with Br^l a Step E required trifluoromethanesulfonic acid. b iRecrystallized from toluene. c Recrvstallized from acetone and pentane. glass 43 Y8.1-2»PYRIDINE CARBOXAMIDE '9" mc(cv3)3 N V NHG(C^)3 Cool a solution of N-(1,1-dimethylethyt)-3-methyl-2- pyridinacarboxamide (38.4 g, 0.2 mole) in dry THF (250 mL) to -40°C 10 and add n-butyl lithium (185 mL, 0.44 mole). Add sodium bromide (1.9 g, 18 rnmol.) and stir for 15 minutes. Add 4-fluorobeirizylchloride (31.8 g„ 0.22 mole) and stir for 2.5 hours while warming to -5®C. Quench the reaction with water and extract the product twice with sthyl acetate, then wash with brine (2X). Dry the organic phase over NagSO^, filter and 15 remove the solvent to give the title compound. (60.0 g, Yield 99%, m.p. 59-61 °C.) 20 CA: B. 342-f4-FLyQROPHFNYjJETHYO-g-PYR8D»Mr= >r 9 Nr^s&i NHC(CH3)3 Heat the title compound of Preparative Example 2A above '(60.0 5,0.2 mole) in POCIg (200 mL) to 110°C under an argon 25 atmosphere for 3.S hours. Pour the reaction mixture onto ice and basify with NaOH (50%) solution. Extract the mixture with ethyl acetate (3x) and. wash with water. 'Wash with brine and dry over NagSO^. Remove the solvent and pass the residue through a coarse SiOg (60-200 mesh) column to givs the title compound as a white solid (40 g, Yield 88%, m.p. 48- 49°C.). i H-BEN/:Of5.61- 5 CYCLQHEPTAfl .g-hlPYRIOIN-11-ONE Cyclize the title compound of Preparative Example 2B 10 above (31.5 g, i 39 mmol) in polyphosphoric acid (1.24 kg) at 200°C for 5.5 hours. Pour onto Ice and basify with NaOH solution (50%). Extract the product with chloroform (3x) and wash with brine. Dry the organic phase with (Ma^SO^ filter and remove the solvent to give the title' compound (20.4 g, yield 64%s m.p. 78-81 °C after recrystallizatioiD from 15 diisopropyl ether).

D. 9-FLUORO-1141 -MFTHY5_-4~ PIPERHDiMYO"6/i 1 • QIHYDRQ-5H-RFN20r5.61CYCl-0PHFPTAn ..2-b1FYRin»N-11 -PL 20 I CHg Dissolve the title compound of Preparative Example 2G above (10.0 g, 44 mmol) in THF (100 mL) and add slowly to a cooled (~40°C) solution of the Grignard reagent prepared from N-methyl-4- 45 chloropiperidine (57.9 mL, 88 rnmol) and magnesium in THF (70 mL).

Stir the mixture for about 1 hour while warming up io 0°C. Quench the reaction with MH^GI solution and extract with ethyl acetate (2X). Wash the organic phase with brine and rfiy over MagSG^, filter and remove 5 the solvent. Purify the residue with flash chromatography and elute with methanol (5%) in GHCIg to give the title compound as white granular crystals. (10.1 g, Yield 70%, m.p. 126-127°C after recrystallization from diisopropyl ether.) 10 E. 9-FL'i JORO-11 -M-MFTHY1 .-4-PIPFRinYI PNEV-n.11 - DiHYDRO-SH-BENZOfSBlCYCI .OHFPTAM .2-hjPYRIDINF 15 Add the title compound of Preparative Example 2D above (7.3 g„ 22.3 mmol) to a mixture of cooled H2SQ4 and GF^SOgM (1:1), (146 mL). Stir the reaction mixture for 0.5 hours at ice bath temperature and then at room temperature for 1.5 hours. Pour the reaction mixture onto ice and basify with NaOH (50%) solution. Extract the product with 20 ethyl acetate (3X) and wash with brine. Dry the organic phase over Na^SO^, filter and remove the solvent to give a crude oil. Charcoal the oil and recrystallize from ethyl acetate and Ssopropyi ether to give the title compound. (5.8 g9 Yield 82%s m.p. 134.5-135.5°G.). 46 F. 9-PU )ORO-11 -f1 -ETHOXYCARBQNYL-A- IFV-fi.11 -niHYDRO-SH-BENZQrS.SICyCLOHEPTAfl .2- blPYRlPINE G02CH2CH3 Stir a solution of th® title compound of Preparative Example 2E above (5.0 gs 16.2 rnmol) and tnetlwSamsne (2.6 g8 28 rnmol) in dry toluene (60 imL) at 80°0 under an argon atmosphere, and add 10 ethylchloroformate (9.8 g5 90 mmol) via a syringe. Stir the reaction at this temperature tor 30 minutes and at room temperature tor one hour.

Filter the reaction and remove the solvent. Pass the residue through a coarse SiOg column (80-200 mesh), and elute with CHCIg to yield th® title compound as a white solid. (4.5 gs Yield 76%s m.p. 112-114°C after 15 trituration with pentane).

G. 9-FU JORO-11 -(4-PHPERIDyHDENEl-6.11-D5HYSRO-5B-i-BENZOr5.6]OYCLQHEPTAn .2-blPYRlDiNE 20 CO^C^CH3 H 47 Reflux the title compound of Preparative Example 2F above (3.83 g510.4 mmol) with KOH (4.6 g) in 50 mL of ethanol/H^o (1:1) for 4 hours under an argon atmosphere. Pour the reaction mixture 5 into a brine solution and extract with ethyl acetate (2X)e dry over Ma2SO^ and filter. Remove the solvent to give the title compound (2.86 g. Yield 90%s m.p. 138-14Q°G.). h. By employing the appropriately substituted benzyl 10 halide listed in Table 4 in place of 4-fluorobenzyl chloride in step 2A above, the desired products shown in the second column of TABLE 4 below are prepared by employing basically the same process as described in steps 2A-2G. Workup time is determined by either TLC or HPLC. fln some instances purification of the product by chromatography 15 is necessary. 48 halide CI Br x.

X, x; TABLE 4 Product of steoG ip4 lP-i R3 H H CI m.p. 134-135°Ca 138-140°Gb 120-122°Cb Recrystallteed from ethyl acetate and pentane.

Triturated with pentane.

PREPARATIVE EXAMPLE 3 5 A. 6.11 -DIHYPRO-11 (i -METHYL-4-PIPERIPYUIPENEV 5H- BENZQf5.6lCYCLQHEPTAf1 ..2-clPYRIPINE The compound 5,6-dihydro~11H-benzo[5y6]cyclohepta[1 s2~ c]pyridin©-11-one, may be prepared by following the (methods described 10 in U.S. Paten! Mo. 3,419,565. This ketone may be converted to the title compound by the methods previously described in Preparative Example 2S steps D and E. 49 B. 11 -(1-CYANO-4-PIPFRIDYL8PI 5H-BENZ0f5-B10YCl OHEPTAfl ^-n'lPYRfPIME To a solution of 400 mg {1.35 mimole) of m-(1-methyl-4- piperidyiidene)-6,11-dihydm-5|l-ban20[5s8](^fd0h@pta[1,2-c]pyridine in 5.0 mL of benzene at room temperature and under an argon 10 atmosphere was added dropwise a solution of 168 Rig (1.59 rnrnoSe) of cyanogen bromide in 4 mL of benzene. After 30 min. the mixture was poured into water and extracted once with EtOAc. The organic layer was isolated, washed once with brine, dried over MagSQ^, filtered, and concentrated in vacuo. The residue was purified via flash 15 chromatography [2.5% CH3OH in CH^Cy to give 150 mg (37%) of the title compound as a solid: m.p. 212~214°G. 50 0. 11-(A-PIPFRinYI .IDENB-6.11 -DIHYDRO-5H- .SICYGLQHEPTAfl .2-cTPYRIDINE 5 A snixture of 140 mg (0.46 mmole) of 11-(1-cyano-4- piperidy Sidena )-S J 1~dihydrQ-5H«b0rs2o[S38Jcyc!ohepia(152~c]pyridirie in 20 imL of 30% aqueous HCI was refluxed for about 22.5 hrs. Th® mixture was poured into ice water, basified with 25% aqueous MaOH, 10 and extracted twice with CH^CL*. The combined organic portions were dried over Ma^SO^, filtered, and 'concentrated In vacuo. The product was purified 'via flash chromatography [5% CH3OH saturated with NHg in CHgCy to give 95 mg (75%) of the title 'Compound as a glass. 15 PREPARATIVE EXAMPLE 4 A. 8-CHLORO-11 H-BENZOrS.61CYCLOHEPTAri -2- blPYRiPIM-11 -ONE Reflux a mixture of 8-chloro-5sS-dihydro-11H-benzo[5,6]cyclohepta(192-b]pyridin-11-one (25.99 g9 0.107 mol.), recrvstallized fM-bromosuccinimide (21.35 g, 0.120 mol) and 167 mg 51 (0.102 mmol) of azobisisobutyrylnitrile (AiBM) in 400 mL of carbon tetrachloride under an argon atmosphere for 1.25 hours. Cool the solution slowly io 50°C and filter off the resultant precipitate.

Reflux the precipitate with 1,8-diazabicyclo[5.4.0]undec-7- 5 ene (DBU) (20 mL, 0.134 mol) in CH^CIg (400 mL) for 1 hour Wash with water (3X), dry over magnesium sulfate, filter and concentrate in vacuo. Recrystallize the crude product from CH^Ciytoluene to give the title compound as colorless needles (8.93 g, yield 35%). 10 B. 8-CHLQRO-11 -(1-METHYL-4-PIPERIDINYLV-11H- 15 To a mixture of 22 mL of 0.5IMI Grignard reagent of iN- rnethyM-chloropiperidine (11.0 mmole) in THIF at 45°C and under a nitrogen atmosphere was added dropwise over 15 min. a solution of 1.06 gm (4.39 mmole) of 8-chloro-11H-benzo[5s8]cyclahepta[1#2- b]pyridin-1-one in 23 mL of dry THF. After 2 hr. 40 min. the reaction 20 mixture was poured into water and extracted three times with ethyl acetate (EtAcO). The organic portions were combined, washed two times with brine, dried over ygSO^, filtered, and concentrated in vacuo.

The residue was purified via flash chromatography [10% CHgOHl in OHgCy to give 970 mg (65%) of the title compound as a glass. 25 52 G. 8-CHi ORO-11 -f1 -METHYL-4-PIPER1PIUDENEV11H-RFN?Of5.61GYG( OHFPTAfl .2-blPYRlDINE CHCH3 5 A mixture of 847 mg (2.48 mmole) of 8-chioro-11-(1-methyl-4-piperidiny!)~1 1H"benzo[5a6]c¥clohepta[1,2-b]pyridin-11-ol sn 5 rnL of concentrated sulfuric acid and 5 mL of trifluoromethanesulfonic acid was heated at 70°C for 4.1 hr. The mixture was cooled to room 10 temperature, poured into Ice cold 30% aqueous KOH, and extracted three times with OHi^Clg. The organic portions wer© combined, washed once with water, dried over MgSO^, filtered, and concentrated in vacuo to yield 755 mg (94%) of the title compound as a glass. 15 D. 8-CHLQRQ-11-f1 TRlCHLOROFTHOXYOARBONYLY-4-PIPERIDYIJDENEi-HH- ■ BFNZQrS.filCYCLQHEPTAM .2-falPYRIOlNE 53 To a mixture of 755 mg (2.34 mmole) of 8-chloro-11-(1- methyl-4-piparidylidene)~11 H~benzo[5eS]cyclohepta[182-b]pvridine and 1.5 mL of trieihylamifia in 25 mL of dry toluene at room temperature and under a nitrogen atmosphere was added 650 kjJL (4.72 mmole) of 2,2,2- 5 trichloroethyl chloroforrnate. The mixture was then heated to 90°C.

Additional amounts of the chloroforrnate (500 p,L and 300 p,L) and triethylamine (1.0 mL each time) were added to the mixture after 2 hr. and 3 hr. 40 min., respectively. After a total reaction time of 5 hr. the mixture was poured into water and extracted three times with 10 The combined organic portions were dried over MgSO£s filtered and concentrated io, vacuo. The residue was purified via flash chromatography [1.5% GH3OH in CH^Cy to afford 839 mg (56%) of the title compound as a glass. 15 E. B-CHLORO-11-(4-PHPFRIDYUDENFV.11H- BENZOTS-filCYCl ..OHFPTAfl .2-WPYR1DINE 20 A mixture of 210 mg (0.434 mmoUe) of 8-chloro-l 1 -[1 - (2,2s2-trichloroethoxycarbonyl)-4»piperidylidene]-11H- benzo[5s6Jcyclohepta[1 e2-bjpvridine and 526 mg (8.05 mmole) of zinc dust in 4 mL of acetic acid was. heated at 60-70°G. After 2 hr. 20 min. another 547 mg (8.37 mmole) of zinc dust was added. After another 30 25 min. the mixture was basified with 10% aqueous NaOH and extracted four times with CH^GI^. The combined organic portions were washed once with water, dried over iMgSG4s filtered, and concentrated in vacuo. 54 The residue was purified via flash chromatography |5—>6% CHgOH/MHg in CHCy to yield 71 mg (53%) of the title compound as a, glass.

PREPARATIVE EXAMPLE 5 5 A. 5-METHOXY-8-CHLORO-11H-BFNZOr5.B1CYCLQHFPTAri .2-b1PYRIPlN-11-ONE B. 6-METHOXY-8-CHLORO-11H- 10 BENZQfS.SlGYCLQHEFTAf 1.2-blPYRIPIN-11-ONE 15 Add Br^ (5.10 mL, 99 mmol) to a mixture of 8-chloro-l 1H- b@nzo[5,6]Qfclohepta[1,2-b]pyridin-11-one (8.15 g, 33.7 mmol) and powdered AgNOg (23.19 g, 137 mmol) in 300 mL of dry methanol at room temperature and under an argon atmosphere. After 8 hours, add additional AgMO^ (5.90 g, 34.7 mmol) followed by additional Br? (1.7 20 mL, 33.0 mmol). After 0.5 hours pour the mixture into water and extract (4X) with CHgClg. Combine the organic phases, dry over magnesium sulfate, filter and concentrate in vacuo to give a mixture of the crude bromo ethers.

Dissolve the crude product 5n CHtgGig (200 mi_) at mom 25 temperature and place under an argon atmosphere. Add PBU (20 mLs 134 mmol) and reflux for 1.3 hours. Add additional DBU (10 mL, 67 mmol) and reflux the mixture for an additional hour. Pour the mixture into water and extract (3X) with ChvCI9. Combine the organic phases, wash with water and dry over magnesium sulfate. Filter and concentrate 30 in vacuo. The two isomeric vinyl ethers, title compounds A and Bv are 55 separated via flash chromatography [40%-»7S% ethyl acetate in hexanes] and recrvstallize from ethyl acetate hexanes to give title compound A (1.51 g, 14.3%s mp 156 to 158°C) and title compound B (3.68 g, 35%, mp: 181-162°C). 5 C. 5-METHOXY-8-CHLORO-11 -f 1 -METHYL-4-PlPPRiDINYP-11 H-BENZOr5-61ftYOI .OHEPTAn .2-blPYRIDIN-11-OI Add a 1.5 Ml Grignard solution of N-methyl 4- chloropiperidine (150 mP„„ 22.5 mmol) on IMF dropwise over a-7 minute period to 5-methox\f-8-chtoro-11 Jti~benzo[5,6]cyclohepte[1,2-blpyridin- 15 11-one (5.00 g, 18.4 mmol) in IHF (70 mL) at 0°C and under an argon atmosphere. Quench the reaction after 30 minutes with a saturated solution of NH^CI (pH 8) and extract (3X) with CHCS^. Combine the organic portions, mrash with brine, dry over sodium sulfate, filter and concentrate an vacuo. Purify via flash chromatography (5% GIHgQIH in 20 CHgCI^) to give the title compound (3.60 gs 53%) as a solid. The solid may be rectystallized from isopropyl ether to give a whit® powder (mp: 168-170°C). 1 t 56 0. 8-CHj QRQ-11-(1~METHYL-4-PIPERIDYLIDENEV-6-1 1-PIIHYORQ-5H-BEN?!Of5.6lCYCLOHEPTAf1 ^-bTPYRtPHN-S-QNE: Dissolve 5-imethoxy-8-chloro-11 ~(1 -imethyl-4-piperidinyi)-* 11H-benzo[5,6jcyclohepta(1,2-b]pyridin-11-ol (4.26 g) in CH^OH (6 mL) at 0°C under an argon atmosphere. Acid slowly a cooled solution of 10 92% aqueous HgSO^ (54 mL)„ Allow the mixture to warm to room temperature for 35 minutes. Poor the solution onto ice, basify with aqueous NaOH (25%), and extract with methylene chloride (3X). Combine the organic portions, wash with brine and dry over sodium sulfate." Filter and concentrate an vacuo.. Triturate th® residue with 15 asopropyS ether to give an intermediate, 8-ChIoro-6e11 -dihydro-11 -(1 -imethyl-4-piperidirsy|)-5s11 -epoxy™5/+benEo[5(,6]-cycloheptan s2-b]pyridin-5-ol as a white solid (3.58 g., 92%, m.p: 170 to 174°C as HQ salt).

Dissolve the intermediate compound (3.58 ge 10.0 mmol) In 20 trifluoromethane sulfonic acid (50 rnL) and heat to 45°G under an argon atmosphere for 3 hours. Pour the mixture onto oce, basify with aqueous NaOH (25% wN)s and extract with CHCl^ (3X). Combine the organic portions, wash with brine and dry over sodium sulfate. Filter and concentrate in vacuo. Chromatograph on silica gel (5% CHgOH in 25 0HpC\9) to give the title compound as an off white solid (1.703 g, S0%9 58% based on recovered starling material). An analytical sample was 57 prepared by recrystallization of the product with ethyl acetate/isopropvl ether (mp: 1S2-163°C).

E. FTHYL-4-ffl-CHI..ORO-fi-FTHOXYOARBONYLOXY- 5 11 H-BFN>T)fB.61CVCLOHEPTAIi .?-h1FYRiOiN-11-Yfl .1PENEM-PIPERID1NF- CARROXYI ATE 10 Dissolve the 8-chloro-11 -(1 -methyI-4-piperidyKdene)~6,1 1 - dihydro-5H-ben2o[5s6]cycloh@pta[1s2-b]pyrjdira-5-ooe (817 mg, 1.82 mmol) and tsiethylamine (0.50 m 3.58 mmol) in toluene (12 mL) at 80°C under an argon atmosphere. Add dropwise over 2 minutes ethyl chloroforrnate (0.87 mL, 9.10 mmol). After 25 minutes coo! the mixture to 15 room temperature, filter, and concentrate jn vacuo. Purity th© crude product via fiash chromatography (1% CHgOH in CH^CL,) to yield the title compound as a glass (834 mgs 98%). 58 F. a-CHLORO-11 -f4-PIPERIDYL8DBNFV-6.11-D8HVDRO-SH-RFtVUZOrS-filOYOI .OHEPTA41 .g-h1PYRIDIN-&-ONE 5 Mix ethyl 4-(8--ch!!oro-5-@thoxycart)onytoxy~11M~ benzo[5f6]cyclohepta[1,2-bJpyddi-11 -ylidene)~1 -piperidiine carboxvlate (897 mg„1.91 mmol) and aqueous IKOH (20 mL, 13% w/v) in sihanol (15 mL) and reflux under an argon atmosphere for 25 hours. Pour the 10 mixture into water and extract with CHCIg (3X). Combine the organic portions, wash with brine, dry over sodium sulfate, filter, and concentrate in vacuo. Purify the residue via flash chromatography (2% CHgOH saturated with NHg in CM2CI9) and triturate with isopropyl ether io give the title compound as a white solid (417 mg, 57%, mp: 194-196°C 15 (dec)). 59 G. 5-HYDRQXY-8-OHLQRO-11 -f4-PIPERIPYLHDENF)- 6.11 -n8HYDRO-5H-RFN7!OfSfi1CYOI_QHEPTAri ,2-blPYRIPINE Mix 8-chloro-11-(4-piperidylidene)~6,1i l-dihydro-SH- lhenzo[59S]eyclQhepia[152-b]pyridin-5-ane (400 rng51.23 mmol!) in CHgOH (20 mL) at 0°C under an argon atmosphere, and add an 3 portions NaBH^ (total 231 mg„ 6.10 mmol). After 30 minutes, pour the 10 mixture into water and extract (3X) with ethyl acetate. 'Combine the organic portions, wash with brine, dry over sodium sulfate, filter and concentrate In ISfiya. Triturate the solid with isopropyl ether/ethyl acetate to give the title compound as a white solid (351 mg, 87%). 15 H. By using a similar procedure to thai described an Parts C through G above of Preparative Example 5„ one can prepare 6-hydroxy-8-chloro-11-(4-piperidylidene)-6s11-dihydro-5H-beri20|S58|cycl0hepta[192-hJpyridine from 6~methoxy-8-chloro--1l IJi-benzo[5s6lcydoheptai192-b]pyridin-11-one of in Part B. However, in Part 20 D of Preparative Example 5S one may use the following procedure in its place: A mixture of 2.00 g (5.39 mmol) of 6-methoxy-8-chioro-11- (1-methyl-4-piperidinyl)-11H-benzo[5,6]cyclohepta[1 s2-b]pyridin-1 l-ol in 87% aqueous sulfuric acid was stirred at room temperature and under 25 an argon atmosphere. After 30 min 30 mL of trifluoromethanesulfonic acid mras added and the mixture was heated to 115 °C. One hour later 60 the mixture was cooled to room temperature, poured onto ice, basifiad with 5% aqueous sodium hydroxide and extracted with methylene chloride (2X). The combined organic portions were washed with brine, dried over NagSCU, filtered, and concentrated in vacuo to give 1.41 g of 5 S-chloro-5,11 -dihvdro-11 -{1 -meihyl-4~piperidinyiidene)-8,W-benzo[5,8]|cyelQhepia-|i 1 ,2-b]pyridin-6-one. The material mfas recrystallized from ethyl acetate/isopropyl ether to give 1.12 g (81%) of the ketone as a granular solid: mp 181 -183 °C. 10 PREPARATIVE EXAMPLE 6 A. 1 ? S TRiMFTHYi -4-CHLOROPSPFRiniME CVk 15 The starting material, 1 ^.S-trimethyM-piperidinol, may be prepared by the method disclosed in Archi Kern. Volume 27e pages 188- 19.2 (1955). To a cooled (ice-bath) solution of 1,2584rimethyfl-4- piperidinoi (12.2gv 85.3 mmol) in 120 mL of dry benzene was slowly 20 added thionylchloride (17 mL, 233 mmole). Hie dark reaction mixture mfas then warmed to 70°C for 20 min. The reaction mfas cooled and then suspended in water followed by filtration. The filtrate was extracted once with diethylether. The aqueous layer was separated and then basified with 30% NaOH solution. The product was then extracted twice with 25 OIHgGI^, washed once with brine, dried (MagSO^), filtered and solvent removed to give a crude brown liquid which mfas distilled (2-4 mmHg, 62-64°C) to give the title compound (8.0gs 58% yield). 61 B. 8-CHLORQ11 -n .PS-TRjMETHYL-4-PIPERIPINYLY-6-11 -DIHYr)R0-5H-BENZ0r5.610YQL0HEPTAf1,2-b1PYR8DIN-11-QL n" Yv / )-ch3 \—-N ch/ xch3 5 The chloride, 1 s2sS4rimeihyl-4-chloropiperidines (4.2 gv 26 mmol) was slowly dripped into a solution of dry THIF (18 imL) containing Mg (633 rngs 26.3 mm). The Grignard reagent was then formed after heating for 6 hours at 70°C. 10 To a cooled (iee-bath), stirred solution of 8~ehloro-5s6- dihydro-1iM-b@nzo[5s6]cyc!oh9pta[1s2-fojpyridio-11-Qne {6.3 g5 26 mmol) in THF (50 mL) was added the above Grignard reagent. The reaction was allowed to stir for 1 hr. at this temperature and then quenched with NH^CI solution. The product was extracted 3X with ethyl 15 acetate, washed once with brine, dried (Na2SO^)» filtered and solvent removed io give a crude brown material which was chromatographed to giv® the title compound (5.1 g, 53% yield) as a yellowish glass.

O 62 C. B-r,Ht ORO-11-M-METhYL-m-g.6-DIMETHYL-4-PIPPR1DYUPENR-6.11 -n(HYDRO-5H-BENZOf5.61CYCLOHEPTAn .2-blPYRIDINE AND TTHF F ISOMER THFREOF M^CHg A mixture of 8-chioro-l 1-(i 5258-tdmsthyl-4-piperidinyl)~ 6J1^ihydro-5H-benzo[5,6]cycIohepta[1,2-b]pyridin-11-ol (5.0 g, 14.1 mmol) in 85% HgS04 (100 mL) was heated in an oil bath (S0~6S°C) for 10 3 hours. The reaction was cooled and diluted with water followed by basifieation with 25% aq. NaOH solution. The crude product was extracted -with CH^CI^, washed with brine, dried (Na^SO^), filtered and solvent removed. Purification and separation of the E and Z isomers via chromatography (2% 5% MeOH saturated with NHg in CHgCy gave 15 a fraction of the pure Z isomer (300 mg, 8%) and a fraction containing a mixture of E and Z isomers (4.18 g, 82%). 63 D. fl-ftm ORO-11-11 -OYANO-fZ)-2.6-DIMETHYL-4-PIPFRi'DY! .IDENE1-6.11 -niHYDR0-5H-BEN70f5.61GYCL0HlFPTAri ?~ blPYRIPHNE A solution of 300 mg (0.85 mmol) of S-chioro-11 -(1 -rneihyl- (Z)-2,,S-dimethyS-4-piperidyiidena)~8811 -dihydro-SJU- i3@n2o[5/8]QfGlohapta[182~b]pyridine in benzene (4,5 mL) was slowly 10 dripped into a stirred solution of BrCM (133 mgs 1.2 inrirraol) so benzene (4.5 mil) at room temperature. This was allowed to stir for 2 1/2 hr under argoa The reaction mixture was suspended between water and ethyl acetate (EtOAc), The EtOAc layer was washed with brine and dried (NlaaSQ^). After filtration the solvent was removed and the crude 15 material was chrornatographed (3% CH3OH in CH^CS^) to give the title .compound (251 mgs 81% yield). r 64 E. fi-CriLORO-11 -IrZ)-P.6-DIMETHYL-4-PIPFR8DY8 iPFNEVS/i 1-niHYnRO-5H-BENZOr5.61CYOLOHEPTAf1.2-blPYRIPINF N OIHg A mixture of 8-chlom-11-(1-cyanG-(Z)~2,6-dimethyl-4- pipelidyl^dene)^^6,1 1 -dihydro-5|i-benzo[5s0]c¥ctohepta[1 s2-b]pyridine (200 mg„ 0.55 mmol) m 80% HOI (20 mL) was allowed to reflux for 7 10 hours. The mixture 'was cooled and than basified with 25% NaOH. The product mras extracted with GHgClg (2X), separated,, washed one® with brine, dried (MaaSO^), filtered and solvent removed to give the title compound (174 mgs 93% yield) as a white glass. 20 F. By following similar procedures in steps D & IE above9 8-chloro-11 -(1 -methyI-(E)-2,6-dimethyI-4-piperidylidene)-6,11 -dihydro-SH- benzo[5s8]cyclohepta[1s2-b]pyridine was converted to 8-chloro-11-((E)~ 286"dimethyl-4-piperidylidene)-6s11-dihydro-5H-benzo[5,8]cyclohepta[ 192-b]pyridi ne. 65 PREPARATIVE FXAMPI F 7 A. 3.5-DIMETH Yt. F YRIPINIUM N-OXIDF lw Q© A solution of 285 mL (1.31 mol) of 35% peracetic acid was slowly added to a stirred solution of 149 g (i .39 mol) of 3,5-dimethylpyridine during which the temperature rose to 85°C and was 10 maintained at this temperature during addition. After the temperature of the mixture dropped io about 35°C the reaction was stored at 5°C overnight After partial removal of 185 ml of acetic add via distillation under vacuum, the reaction was 'washed with NaHSO^ solution and 15 then neutralized with 10% NaOH solution to pH of about 7., The product was extracted with CHgCI9 to give the title compound as a white solid (yield 142 g9 83%).

B. 1 -METHOXY-3.5"DIMETHYLPYRIDiNCyM METHYL 20 SULFATE 25 Dimethylsulfate (42.0 g, 0.33 mol) was slowly added to 41.0 g (0.33 mol) of 3,5 C. 2-CYANQ-3.5-P1MFTHYLFYRIDINE 'INT | CH3SO. OCH3 To a cooled (0°G) solution of sodium cyanide (49.0 g, ©.999 imol, 3.0 eq.) in 135 mL of water (air free) was dripped 1-methoxy-10 3,5-dimethyl pyridinium methyl sulfate (83.0g, 0.33 r=-;al) in 100 rnL water (air free) in 1.25 hr., keeping the temperature below 3°G. The reaction mixture was stored at about 3°C overnight. The mixture mfas filtered and washed with water to give 40g of the title compound. An analytical sample was recrystallized from asopropyl ether and pentane (4:1) (m.p.: 15 61-62°C). 20 D. N-f 1 .1"DlMEThlYLETHYL>-3.5-PiMETHIYL-2-PYR[PINE CARBQXAMIPE l.A •hi *CN M^V:; "C(CH3)3 o 25 To a stirred solution of 20.3 g (0.153 mol) of 2-cyano-3,5-dimethylpyridine in 100 mL of 20 mL of conc. sulfuric acid within 10 minutes, followed by 20 mL of t-butanoi over an additional 15 minutes. The solution was warmed at 75°C for 30 minutes after -which it was cooled to room temperature and basified with 25% NaOH. The product was extracted 3X with EtOAc (600 mL)„ which was combined and 67 washed 1X with brine, dried (NagSO^), filtered and concentrated in vacuo to give the title compound (31.26 g) as a yellowish oil.

E. 8-CHLQRO-3-MFT1I-3YB.-11 44-PMPERIDYj .8DEh8FVfi.11-5 DiHYDRO-5H-BEMZOrB.61CYOLOHi-PTAri.2-hlPYRSntMF Bv substituting in step 18 above ^1,1^methyletliiyl)-3,5- 10 dimethyl-2-pyridine carboxamide for W-(1 S1 -dimeihyleihyl}~3~metlriyl-2-pyridine carboxamide and employing basically the same methods as steps B through G of Preparative Example 1, one obtains 8-chloro-3~ methyl-11-(4-piperidyliciene)-6s11-dihydro-5ii-benzo[5,6]cyclohepta[1 :Z~ bjpyridine. Reaction times are determined by TLC or HPILC. 15 PREPARATIVE EXAMPLE 8 A. 1 -Ci -METHY1 .-4-PlPFRIDINYL\-1 PHE N YLETH YE .V2-PYRIPYL1METHAN QL 20 1 1 GHg CH3 68 To a mixture of 5.0 g (16.2 rnmole) of (1-methyl-4- piperidiriyl)[3-(2~phenylethyl)~2~pyridinylJmethanon@ (which can be prepared in the same manner as described in Preparative Example 1 5 Steps ,-VD except using benzyS chloride in place of meta-ehlorobenzyl chloride) in 70 mL of methanol was added portionvvise 0.8 g (21.1 mmole) of sodium borohydride. The next day the solution was concentrated in vacuo to give a slurry which mras dissolved in water and extracted with CHGIg. The combined organic portions were dried over 10 MgSO^, filtered, and concentrated M vacuo to provide a liquid which was distilled (bp 190-195°G <§> 1 mm Hg) to give 4.4 g of the title compound as a viscous oil.

B. 11-1 -METHVll ."4-PiPFRiDY? .V6.11-D1HYPRO-5H-15 RFNZOr5.filCYCLOHEPTAn -?~blPYRPDINF* A mixture of 3.5 g (11.3 mmole) of 1-(1-methyl-4-piperidyl)-20 l-[3-(2-phenylethyil)-2-pyrfcfyQmethanQl and 200 g of polyphosphoric acid was heated between 160-170°C tor 13 hours. The mixture was cooled to room temperature, poured 5mto water, basified mfith aqueous NaOH and extracted with ether. The combined organic portions were concentrated in vacuo and the product recrystallized to give the title 25 compound as a white solid, (mp 111 -114°C). 69 C. 11 ~(4-PlPERinya V8.11 -DiHYDRO-nH-i ,2-BIPYRIOIME.

S* J N in a similar manner to that described in Preparative Example 1, Steps F-G, 11"(1»methyl-4-piperidyl}-6s11~dihydro-5H benzo[5f6]cyclohepta[1,2-b]pyridine can be converted to 11 "(4-piperidyl)~6,11 ~dihydr0-5H-beri!20p>/ijcyd0hepta(i ,2-b]pyridin@.

PREPARATIVE EXAMPLE 9 A. 8-CHLQRQ-5.6-DIHYDRQ-11H- BEMZQr5.61CYCLOHEPTA-ri .2-B1FYRiPIN-11-ONF N-OXIDE„ To a mixture of 25.1 grams (G.103 mole) of S-chloro-5,6-dihydro-11H~benzo[5,6]cyclohepta[1,2~b]pyrfclin-11-one sn 175 mi of dry methylene chloride at 0°C under an argon atmosphere was added 20 dropwise over 70 minutes a solution of 24.12 grams of 3- chloroperoxybenzoic acid in 150 mi of methylene chloride. After the addition the solution was stirred for 1/2 hour after which the ice bath was removed. After two days the reaction mfas poured into 1.0 M aqueous sodium hydroxide and extracted with methylene chloride. The organic 70 portions were combined, washed once with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The resultant product mras triturated with isopropyl ether and filtered to provide 2S.8 grams (96%) yield of the title compound. 10 B. 2.8 OiCHLORQ 5.5-PiHYP:)RO i 1H-BENZOf5.6TCYCLOHEPTAri.2-BTPY ' DIOHLORO-5.8-PIHYDRO-11 H-BFNZOT5 -61CY CLOHEPTAf 1.2-blFYRHDIN-11-QNE.

V"C' To a mixture of 29.13 grams (112.2 rnmol) of the title compound from Preparative Example 9A above, iin 40 ml of dry 15 methylene chloride at 0°C and under argon atmosphere was added 500 ml of 1.0 M SOjtCb dropwise over 1 hour. The ice bath 'was then removed and the reaction stirred at room temperature for 1 hr and then refluxed for seven hours. The mixture was poured onto 1.0 N aqueous NaOH and extracted three times with CHaCb. The organic portions 20 -were combined, dsied over SW'igSO^ filtered and concentrated in vacuo to yield a product which was purified and separated via flash chromatography to yield the two title compounds. 71 C. 4-f2 ■8-DiCHLQRQ-S B-01HYDRO-11H-BEN?Or5.61QYCi OHFPTAM P-blPYRIDltNM1 -YUDENE^PiPERIDINF AND 4~f4 S-niCNi .ORO-5.fi-DIHYDRO-11 H-BEN?Or5.61CYCI .OHFPTA-fl „2-b1PYRIDIN-11 -Y' VCI (1 I 10 By following essentially the same procedure as that described in parts D-<3 of Preparative Example 2 above, the 298~dieh!oro and 4,8-dichloro products of Preparative Example 98 above were converted to the corresponding title compounds. 72 PRFPARAT1VF FXAMPLE 10 A. 4~m-CHLQRO-2-HyOROXY-B.6-PIHYDRO-11H-BENZOT5.fi1QYCl OHEPTAfl .2-b1PYRIPlN-11 -YLiDENElPIPERIPINE. 5 A mixture of 180 mg of the 2,8-cfehloro title compound of Preparative Example 9-C above, 7 ml of 2.0 N aqueous sodium 10 hydroxide and 7 ml of methanol were heated at 160°C under a nitrogen atmosphere io a sealed pressure vessel for two days. The vessel was then cooled to room temperature. The mixture was poured into water and extracted three times with methylene chloride. The organic portions were combined,, dried over magnesium sulfate, filtered and concentrated 15 in vacuo to provide a residue which was triturated with isopropyl ether/methylene chloride to provide 85 mg of the title compound as a white solid.

B. By using the procedure of Preparative Example 10 20 above, one can make substitutions of other groups at the 2-position by employing the appropriate nucleophile in place of sodium hydroxide (e.g. dimethylamine, ammonia, potassium thiolate, etc.). < 73 PRPPARAT1VE EXAMPLE 11 5 A. 4-f8-CHLORO-4-METHIOXY-5.6-PIHYDRO-11H- BENZOfS .61CYCLOHEPTAf 1.2-blPYRIDlN-l 1 -YLIDENE1P1PERIDINE.

A mixture of 212 mg of the 4,8-dichloro title compound of Preparative Example 9-C above, 7 ml of 2.0 M aqueous sodium 10 hydroxide and 7 ml of methanol were heated at 135°C under a nitrogen atmosphere in a sealed pressure vessel for 18 hours. The vessel was then cooled to room temperature. The mixture was poured into water and extracted three times with methylene chloride. The organic portions were combined, dried over magnesium sulfate, filtered and concentrated 15 in vacuo to provide a residue which was purified via flash chromatography (4~*7% methanol saturated mfith ammonia in methylene chloride) and then triturated with isopropyl ether/methylene chloride to provide 144 mg of the title compound as a white glass. 20 B. By using the procedure of Preparative Example 11 above, one can make substitutions of other groups at the 4-position by employing the appropriate nucleophile in place of sodium hydroxide (e.g. dimethylamine, ammonia, potassium thiolate, etc.). 25 PREPARATIVE EXAMPLE 12 A. By substituting the compound listed in Column 1 TABLE 5 below for 3,5-dimethylpyridine in Preparative Example 7 above and 74 following basically the same procedure (steps A-E), the compounds listed in Column 2 below can be prepared. Mote that the addition of the nitrile group to the pyridine in step C. of Preparative Example 7 can result in the formation of other undesirable isomers which can be removed via flash chromatography. 75 TABLE 3.

Co Huron 1 Column 2 ^NT « fl ID h R! B! IPg'l'll'W) H H Ci Gs o H H CH % Sr H H H CH, 76 PRFPARATIVF EXAMPLE 13 A. 3-(1.1 -PIMETHYL-1 -ETHYL V8-CHLQRO-5.6-DiHYnRQ-11 H-BFN?Of5.filCYCi OHEPTAfl .?-hlPYRIPIN-11 >ONF 5 To a mixture of 20.05 grams (82.28 mmol) of 8-chloro-5,6-dihydro-11M-benzo[5v6]cyclohepia[1,2~b]pyridin-11l-one in 400 ml of dry 10 tetrahydrofuran at -72°C and under an atmosphere of nitrogen was added dropwise over 40 minutes 86.0 ml of 2.7 Ml it-butyl magnesium chloride in tetrahydrofuran. The reaction mixture was slowly warmed to room temperature and stirred overnight. The mixture was then poured into 10% aqueous ammonium chloride and extracted four times with 15 methylene chloride. The combined organic portions were dried over magnesium sulfate, filtered, and eoncentraied in vacuo to give the title compound, along with 8»chloro-11-(1s1-dimethyi-1-©thyl)-8211-dihydro-5H~benzo[5,6Jcycloheptan e2-b]pyriclin~11 -ol These compounds were separated via flash chromatography to give the litis- compound,, which 20 was recrystalfized from isopropyl ether to give 4.37 grams (18%) of the title compound as a white solid.

B. 4-T3-M -1 "DIMETHYL-1 -ETHY1J-8-CHLQRO-5.8-PIHYDRO-i 1 H-BENZOf5.6lCYCLQHEPTAf1.2-b1PYRIDIN-11 - 25 YLiPENElPIPERiPlNE. 77 H By using the title compound of Part A above and applying essentially the same procedure described in parts D-G of Preparative Example 2 above, one can obtain the title compound.

PREPARATIVE EXAMPLE 14 A. 4-fS-CHS-OROS-frDIHYDRO-3-fll -HYDROXY-1 -ETHVi-1-11 H-BENZQf5.61CYCLQHEFTAf 1.2-BTPRYIDIN-11 -YL.1DENE1PIPERID1NE OH H 3-Bromo-8-chloro-6,11 -dihydro-11 -(4~pipeiidylidene)-5U- benzo[5,8]cyclohepta[1 s2»b]pyridine (779.4 mg) in dry tetrahydrofuran (25 mL) was cooled to 7B°C under argon. To this was dripped in n-butyl Dithium (1.76 rnL in hexane, 2.2 eq.) keeping the temperature below -74°C. After stirring for 10 minutes acetaidehyds was bubbled into the solution until the reaction color turned yellowish in approximately 20 minutes. The mixture was allowed io stir for 20 minutes and then quenched with water followed by extraction with methylene chloride. The organic phase was dried (MagSC^) and the filtered. Solvent was 78 removed and the crude product was chromatographed on SiC>2, eluted with 10% methanol satuarted with ammonia in methylene chloride to give 219 mg of the title compound. 5 B. By following essentially the same procedure as described above in Preparative Example 14, but using other elecrlrophiles in place of acetaldehyde (e.g., GOa, ethyl propargvlate, ethyl formate, etc.), one can make compounds which contain a carboxy, a 3~carboethoxy-1=propen-1~yle and formyh respectively, at the 3-10 position.

PRPPARATiVE EXAMPP .F 15 A. B-CHLORO-6.11 -DIHYDRO-11 -HYDROXY-SH-BFN?OrS.fi1CYCLOHEPTAf1.P-B1PYRUDINE 15 To a mixture of 25.03 (103 mmol) of S-chloro-5sS-dihydro~ 11H-ben2o[58S]cyclohepta[1g2-b]pyridin-11-ont@ in 200 mL of methanol 20 at room temperature and under a nitrogen atmosphere was added portionwise over a period of about 1 hour 4.82 g (124 mmol) of sodium borohydride. Occasional cooling with an ice bath was necessajy at times during the addition in order to avoid excessive reflux. After 1.8 (hour the mixture was poured into ice cold water and then extracted with 25 ethyl acetate (3X). The combined organic portions were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from liot isopropyl ether. The remaining filtrate was purified via flash chromatography (20% ethyl acetate in hexanes) to yield more product which solidified ami standing. Both 30 batches were combined io yield 20.41 g of the title compound as a white solid. 79 BFN7Of5.610YCt OHEPTA[1 ^-BIPYRIDINE To a mixture of 13.3 g (54 mmol) of 8-chloro-6,1 1 -dihydro-11-iiydroxy-5H-benzo[5#6]cyclohepta[1B2-b]pyridine in 290 mL of toluene at -15 °G and under an atmosphere of nitrogen was added via syringe pump over a period of 1 hour 6.20 mL (85.7 mmol) of thionyl 10 chloride.The extent of reaction was monitored by TLC (50% ethyl acetate in hexanes). When completed the mixture was poured into 300 rnL of 1.0 N aqueous sodium hydroxide and extracted with ethyl acetate (5X). Th© combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated -So vacuo. The residue 15 was taken up in ethyl acetate, quickly filtered through basic alumina, and concentrated again to yield a product which was triturated with pentane to yield 10.22 g of the title compound as a tan solid. 20 C. 8-CHLORQ-11 -n -PIPERA7INYI V-3.11 -DIHYPRO-•-WYi nMFPTAfl .g-BlFYRIDlNF To a mixture of 10.0 g (37.3 mmol) of 8,11~dichloro~6,11-25 dihydro-5H-benzo[5,6]cyclohepta[1,2~b]pyridine and 1.0 mL of triethylam'me in 200 mL of dry tetrahydrofuran at room temperature and under a nitrogen atmosphere was added 33.0 g of piperazine. The mixture was stirred at room temperature for 22.5 hours and then refluxed 80 10 for 5.5 hours. 8t was then cooled to room temperature, poured into 250 mL of 5% aqueous sodium hydroxide, and extracted with methylene chloride (3X). The combined organic portions were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Tha residue was purified via flash chromatography (2—>5% methanol saturated with ammonia in methylene chloride) to yield the title compound as a glass.

DIHYDRQ-11 H-BFNZOrSfiTCYCLOHFPTAfl .2-MFYRIDIN-1 1-YLIDENEIPIFERIDINE Nl-QXIPE- To a mixture of 5.01 g (16.1 rnmol) of 4-(8~chloro-5s8-dihydro-1lH-benzo[5,6]cydohepta[1 s2-b]pyridin~11-ylidene)piperidine (product from Preparative Example 1, Step G), 2,19 g (15.7 mmol) of 20 isonicotinic acid N-oxide, and 2.33 g (17.2 mmol) of 1- hydroxybenzotriazole hydrate in 30 mL of dry methylene chloride at -15 °C and under a nitrogen atmosphere was added dropwise over 25 minutes a solution of 3.26 g (16.9 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DEC) in 80 mL of dry methylene 25 chloride. The reaction mixture mfas slowly allowed to warm to room temperature. After 3 hours the mixture was poured into a solution of 81 10% aqueous sodium dihydrogen phosphate and extracted three times with methylene chloride. The combined organic portions were dried over IWigSO/j., filtered, and concentrated in vacuo to give a product which was purified via flash chromatography and recrystallized using isopropyl ether to give 1.35 gms (82%) of 1-(4~pyridinyl carbonyl)-4-(8-chloro-5,6-dihydn>-11 H-benzo[5,6]cyclohepta{1,2~b]pyridin-11~ylidene)piperidine N1 -oxide as a white solid (228° G, dec).

FXAMP3 ,F 2 By essentially the same procedure as set forth in Example 1 above but using the amines set foslh in Column 1 below in place of 4-(8-chloro-5,6-dihydro-11H-benzo[5„6]cyclohepta[1,2-bjpyridiim-11 -ylidene)piperidine, one can obtain the compounds Sisted in Column 2 of TABLE 8 below: 82 M££ Column 1 Column 2 R %i I « Rl-W' I ol^S (s^N-^O bi & b3 m as CH3 H H CI HI H t-butyl- H CI H H CH3C(OH)- ■ H CI H H H ' GH3 CI H CI H H CI H H CI H CI H H H CI CI H H Br H CI H HO HI H CI IHI HI H OCH3 GS IHI H H H H CI H H H F F H H H CH3 H EXAMPLE 3 By employing essentially the same procedure set forth Example 1 above but using the amines set forth in column 1 belomf in 83 place of 4-(8-chloro-5,6-dihydro~11 H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine, one can obtain the compounds listed in column 2 of TABLE 7 below: TABLE. 7 Column 1 Column 2 r4 y a h n F F n 5 a H CH .EXAMPLE 4 By employing essentially the same procedure set forth in 0 Example 1 above but using the amines set forth in column 1 below in place of 4~(8-chioro-5,6~dihydro~11 H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine, one can obtain the compounds listed in column 2 of TABLE 8 below: 84 Column Column 7. f \ L , ■s* V n Wn'yV s, ^ N ft v*^' #1 I N-VV on->-O o^v^l 85 Column TABLE 8 CONTINUED Column z a -V-01 J) I r I $»■- ft I // V* £0 f CI CNf^N^C^ H EXAMPLE 5 By employing essentially the same procedure set forth Example 1 above, but using the carboxlic acids set forth in column 1 below in place of isonicotinamic acid IM-oxide 8 one can obtain the compounds listed in column 2 of TABLE 9 below: 86 TA8LE9 Column 1 HOOO^s^C!^ 11 I CHi Column 2 II *%*"■ V^CI 0 63 1 N->-0 CH, SM->-0 .W>-0 5 1 -(4-FYR1D8N YLCARBQNYLV4-f 8-CHt .ORO-5.6-D IIHYD RQ-11H-BENZOTS-SICYCLOHEFTATI .2-WPYRIPIIN-11 -YLIDENE1P1PERIDINE Ml. IM'A-D IQXy D E- To a mixture of 1.35 grams of the title compound from 10 Example 1 above in 15 ml of dry methylene chloride at -i 5°G in under an atmosphere of nitrogen was added in several portions over a period of three and one half hours 649 mg of 3-efitoroperaxy benzoic acid. The mixture was allowed to come to room temperature and stir over night. The reactions mixture was than poured into a solution of 10% sodium 15 bisulfite and extracted with methylene chloride. The combined organic portions were washed with 1.0M sodium hydroxide, dried over magnesium sulfate, filtered and concentrated in vacuo. The product ■was then purified via flash chromatography (20% methanol saturated with ammonia In ethyl acetate) and the appropriate fractions combined 20 and reciystallized from ethyl aoetate/methanol/isopropyl ether to give 707 mg (51%) of 1-C4-p|nislin¥lcamoiiy!)-4-{0-chloro-5,8-dihydro-11|l-benzo[5,6]cyclohepta[1,2-b]pyridin~11 -ylidene)piperidine ,IM4-dioxide as a white powder. 88 EXAMPLE 7 1 -(3-PYRIDINYLCARBONYI.V-4-ffl"CHLQRQ-5-fi-DIHYDRQ-11 H-BFNZOf5-61CYCI .OHEPTAH ,g-BlPYRIDIN-11-5 YUPFNF^PIPERIDINE By employing essentially the same procedure as set forth 10 an Example 6 .above, but using 1-(3-pyridiny8carbonyl)-4-(8-chloro-5,6-dihydra-11 b"-benzo(5,6jfcydoiniepta£i! ,2-bJpyiriidirt-11 -ylide mejpipe ridi ria N1-oxide in place of 1-(4ijyirikiiifiylcartX)nyI)-4-(8-chtoro-5,6-dihydro- 11|4-lb©nzo|5s6]cycioheptap ,2-h]pyriidin-1l 1 -yllidene)piperidine N1oxide, one can obtain 1-(3-pyridinylcait)ony!)-4-(8-chloro-5,6-dihydro-11H-15 benzo[5,6]cydlohepta(1,2-bJpyiidin-l1 -y lide ne) pi pa ridi ne N1 ,N4-dioxide.

Tfn© following are examples of pharmaceutical dosage forms which 'Contain a compound of the invention. As used therein, the term "active compound" Is ysed to designate the 'Compound 89 N+-»~0" FXAMP1 E 8 BEMZ 4-ffl-fiM! ORO-S.fi-D8HYPRQ-3-MFTHiYL~ 111H-.61CYCL.OHFPTAM -2-B1FYRID1N-11 -YLUDENE1-1 -f4-:ARBONY» .1PIPFRIDINF Nl-OXIOE 10 To a mixture of 20 g of 8-chloro-11-(4-piperidyRdene)-6,11-dihydro-3-methyl-5H-benzo(5l6]crydohepta[1 (2-b]pyridine (product from Preparative Example 7„ Step E), 1.39 g of isonicotinic acid N-oxide, and 15 ll .35 g of 1-hydroxybenzotriazoie in 60 mL CH2CI2 at 0°C was added 1.91 g of 1-(3-dimettylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC). The reaction mixture was slowly allowed to warm to room temperature overnight. The reaction mixture was quenched with water, t > 90 basified with 10% NaOH, and extracted with GH2GI2. The combined organic portions were washed with brine, dried over Na2S04, and concentrated m vacuo. The product mfas flash shromatographed using 5% methanol in methylene chloride to give 2.52 g of a product which 5 could be triturated with CIHteCfc/diisopropylether (1:20 parts by volume) to give the title compound as a white solid.

EXAMPLE .9 10 4-fB-CHLQRQ-S.6-DlHYORO-3-METHYI -11H- BENZOrs.filCYOI .OHFPTAfl .g-BIPYRIDIN-11-YL11DENE1-1 -(&-PYRIDiMYi CARBONYI .1PIFERIDINE M^OX5Df= 15 To a solution of 900 mg of the title compound of Example 8 above in 25 imL dry CH2CI2 at 0°C was added 700 mg of m-chloroperoxybsntioic acid in 4 portions 15 minutes apart. The reaction was then continued to stir for 1 hr. The mixture was taken up in CHgCte, 20 washed with 10% WaiHISOs solution, with 10 N sodium hydroxide solution and with brine. It was then dried {N&.2SQ4) and filtered. The solvent was removed under vacuum with a rotavap to give 950 mg of a whit© foam which was chromatographed with SsOa (230-400 mesh, 10% methanol saturated with ammonia in ethyl acetate) to give 689 mg of the 25 title compound as a white glass.

The scope of the invention in its pharmaceutical composition- aspect is not to be limited by the examples provided, since 91 any other compound of structural iormu'a x canbe substituted into the pharmaceutical composition examples.

Pharmaceutical Posaae Form Examples 5 EXAMPLE A No.

Tablets Ingredients mg/%ablet mg/iablet 1.

Active compound 100 500 2.

Lactose USP 122 113 <2^1 %Jo Com Stanch, Food Grade, 30 40 as a 10% paste la Purified 'Water 4.

Corn Starch, Food Grade 45 40 5.

Magnesium Siearate a 7 Total 300 700 Method of Manufacture Nix Item Nos. 1 and 2 on a suitable mixer for 10-15 minutes. Granulate the mixture with Item Mo. 3. Mill the damp granules 10 through a soars© secern (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. Screen the dried granules if necessary and mix with Mem No. 4 and mix for 10-15 minutes. Add Kern Mo. 5 and mix for 1-3 minutes. Compress th® mixture to appropriate size and weigh on a suitable tablet machine. 15 EXAMPLE 8 Gmsulm m 92 mg/capsute 1« Active compound 100 500 2. Lactose USP 108 123 3. Corn Starch, Food Grade 40 70 4. Magnesium Stearate IMF 7 7 Total 250 700 Method of Manufacture Mix Item Nos. 1,2 and 3 in a suitable blender for 10-15 minutes; Add Kern No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine. i 93

Claims (17)

1. CLAIMS 1* A compound having the structural formula 10 A 3> •« A ' 15 I or a pharmaceutically acceptable salt or solvate thereof, wherein: R represents an kl-oxide heterocyclic group of the formula (i) 20 O'i), (iii) or (iv) O if ' 1 $ .A\ IR\ C \-N. Si 25 *10' © * / W - P X V. pflO' 'R11 « N \ e*l I £ N 11/ 30 35 or R represents a straight or branched to C2Q alkyl group substituted with a heterocyclic N-oxide group of the formula (i), (ii), (iii) or (iv) aboves 12 12 one of a bs c and d represents N or HR where R is 0, -CH^ or "(C^J^COgH wherein n is I to 3, and the remaining a, b„ c and d groups are CH, which remaining a, b, c and d groups 1 2 optionally may be substituted with R or R ; 1 2 S;V" and R may be the same or different and each independently represents halo, -CF3, -OR13, -COR13, -SR139 -S(0)eR14 wherein e is 1 or 2, ^(R13)2, N02,-0C(0)R13, ~C02RA3, 94 14 -0C02R a straight or branched C2 to C12 aikenyl group, containing at least one carbon to carbon double bond, a straight or branched C2 to Cj2 aikenyl group, containing at least one carbon to carbon triple bond or a straight or branched to C2q alkyl 5 group, which alkyl group may be substituted with halo, -OR' or io _ 1A ~C09R and which aikenyl group may be substituted with halo, -OR" 13 or -C02R R3 and R4 may be the same or different and each independently 12 3 10 represents H or any of the substituents of R and R , or R and a R' together may represent a saturated or unsaturated Cg-C-j carbocyclic ring fused to the benzene ringt- R^, R®, R^ and R® each independently represent H, -CFg, 15 a straight or branched Cj to C2g alkyl group or a Cg to Ctg aryl group which alkvl or aryl group being optionally substituted with 11 1 1 1"3 -OR , -SR or -N-(R )2» and said aryl group also being optionally substituted with one or more halo, straight or branched Cj to C2g alkyl, hydroxy, straight or branched Cj to C2q alkoxy, phenoxv, 20 CFg, amino, straight or branched Ct to C20 alkylamino, straight or branched to C2Q dialkylamino, -COOR1^ as defined below or -W02! 5 5 in addition, R may be combined with R to represent =0 or =S 7 8 25 and/or R may be combined with R to represent =0 or =S; 9 10 11 R , R and R may be the same or different and each is independently selected from H, halo, -CFg, -0R^3, -C(0)R13, -SR"3, ~S(0) R14 where e is 1 or 2, -N(R13)9, -N09, -C09R13, 30 -0C02R~'e -0C0R , straight or branched Cj to C2q alkyl, Cg to aryl group being optionally substituted with one or more halo, straight or branched C^ to C2q alkyl, hydroxy, straight or branched Cj to C2Q alkoxy, phenoxy, CF^, amino, straight or branched Cj to Cgg alkylamino, straight or branched Cj to C9q dialkylamino, 35 -C00R^ as defined below or ~N02aryl, straight or branched C2 to C19 aikenyl or straight or branched C9 to C.9 alkynyl, which Lc C «=- yo i *3 o alkyl or aikenyl may be substituted with -OR , -SR or -N(R )9 14 lik ^ and which aikenyl may be substituted with OR or SR"'° 95 1 1 R represents H straight or branched C-, to C2g alkyl or Cq to Cjg aryl group being optionally substituted with one or more halo, straight or branched Cj to C2Q alkvl, hydroxy, straight or branched Cj to C2q alkoxy, phenoxy, CF^ amino, straight or 5 branched Cj to C2q alkylami no, straight or branched Ct to C20 dialkylamino, -C00R as defined below or ~N02arvl; 1 d R~' represents straight or branched Cj to C2g alkyl or Cg to Cjg aryl group being optionally substituted with one or more halo, 10 straight or branched Cj to C2q alkyl, hydroxy, straight or branched Cj to C2q alkoxy, phenoxy, CF^, amino, straight or branched Cj to C2q alkylami no, straight or branched C^ to C20 dialkylamino, -COOR1^ as defined below or -N02aryl; 15 15 R represents H or straight or branched C^ to C2q alkyl; X represents N, CH or C; when X represents C, an optional double bond indicated by the 20 dotted lines to carbon atom 11 is present, and when X is N or CH, the double bond is absent; the dotted line between carbon atoms 5 and 8 represents an optional double bond, such that when a double bond is present, A and B 25 each independently represent -R^( halo, -0R^, ~0C(0)R^ or Id -0C09R ' and when no double bond is present between carbon atoms 5 14 and 5, A and B each independently represent H2, -(OR )2, [H and halo], dihalo, [straight or branched C^ to C2g alkyl and H], (straight or branched Ct to C9n alkvl)9, [-H and -0C(0)R*'3], [H 30 and -OR ], =0, [aryl and H], =M0R or -0-(CH9) -0- where p is 13 " 2, 3, or 4 and R , Cg to C^ aryl group being optionally substituted with one or more halo, straight or branched Cj to C2q alkyl, hydroxy, straight or branched C^ to C2q alkoxy, phenoxy, CF^f amino, straight or branched C1 to C2q alkvlamino, straight 35 or branched Cj to C20 dialkylamino, -C00R"® as defined below or -N02aryl and straight or branched C1 to C2q alkyl; and Z represents =0. 96

2. A compound of Claim 1, wherein the double bond between carbon atoms 5 and 6 is absent.

3. A compound of Claim 1 wherein the double bond between carbon atoms 5 5 and 6 is present. 5 6

4. A compound of any of Claims 1-3 wherein R and R are H and 7 ft R and R each independently represents H or alkyl as defined in Claim 1. 10 1 2

5. A compound of any of Claims 1-4 wherein R and R each 13 13 independently represents H, alkyl, OR , NR2 or halo as defined in Claim 1. 3 4 15

6. A compound of any of Claims 1-5 wherein R and R' each 13 13 independently represents H, alkyl, OR , NR2 or halo as defined in Claim 1.

7. A compound of any of Claims 1-5 wherein X represents C and the 20 dotted line thereto is a double bond.

8. A compound of any of Claims 1-6 wherein X represents CH and the double bond indicated by the dotted lines thereto is absent. 25

9. A compound of any of Claims 1-6 wherein X represents N and the double bond indicated by the dotted lines thereto is absent.

10. A compound of any of Claims 1-9 wherein R represents O 35 wherein each of pp and R*® independently represents He alkyl, halo„ OR13 or M(R13)2 as defined in Claim 1.

11. A compound of any of Claims 1-10 wherein R represents \ 97 - Nr"" o

12. A compound which is: 35 98 99 la 100 101 102

13. A pharmaceutical composition comprising a compound of formula I as defined in Claim I in combination with a pharmaceutical^ acceptable carrier. 5

14. A compound of formula I as defined in Claims 1 to 12, for use in treating allergy.

15. A compound of formula I as defined in Claims 1 to 12 for use in treating inflammation. 10 15.

16. Use of a compound of any of Claims 1-12 for the preparation of a pharmaceutical composition for the treatment of allergy or inflammation. 15

17. A process for producing a compound having structural formula I as defined in Claim 1 comprising the steps ofs a) reacting a compound of formula II below with a compound of formula RCOOH in the presence of a coupling agent to produce a compound of 20 formula I 25 30 Fr* + iirmJDO I R6- i j\ 'fr* N 35 y 103 b) reacting a compound of formula II with a compound of formula III in the presence of base to produce compounds of structural formula I 10 11 I